Evaluating the potential of ethyl cellulose/eudragit-based griseofulvin loaded nanosponge matrix for topical antifungal drug delivery in a sustained release pattern.

Fungal infections are very alarming nowadays and are common throughout the world. Severe fungal infections may lead to a significant risk of mortality and morbidity worldwide. Sustained delivery of antifungal agents is needed to mitigate this problem. In the current study, an attempt has been made to formulate griseofulvin-loaded nanosponges using the quasi-emulsion solvent diffusion technique. For characterization, griseofulvin loaded nanosponges were tested by different instrumental techniques such as optical microscopy, scanning electron microscopy (SEM), powder X-ray diffractometer (PXRD), Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), and transmission electron microscopy (TEM). The antifungal activity of the nanosponges was assessed against Candida albican strain using the agar well-diffusion method. Finally, the drug-loaded nanosponges' in vitro sustained release activity was evaluated. FTIR spectra showed no chemical interference between the drug and polymers. Some of the peaks of the drug are not visible in the FTIR spectrum, which suggests drug entrapment. PXRD data showed that the drug lost its high crystallinity when entrapped in the nanosponge matrix. From the morphological studies via SEM and TEM, a brief idea of the surface morphology of the nanosponges was obtained. The small pores throughout the structure proved its high porosity. The antifungal sensitivity assay was successful, and a zone of inhibition was observed in all the formulations. The in-vitro drug release study showed sustained behaviour. The sustaining effect was due to the polymer and cross-linker used, which gave rise to a porous scaffold matrix. From the results, it can be concluded that griseofulvin-loaded nanosponges can be used for antifungal drug delivery against various topical skin infections.

Novel griseofulvin zinc nanohybrid emulsion for intensifying the antimicrobial control of dermatophytes and some opportunistic pathogens.

Dermatophytosis is a critical sort of skin infection caused by dermatophytes. The long-term treatment of such skin infections may be improved through the application of nanotechnology. This study aimed to prepare griseofulvin zinc Nanohybrid emulsion (GF-Zn-NHE) to improve griseofulvin activity against dermatophytes and some opportunistic pathogenic yeasts and bacteria. The GF-Zn-NHE is prepared by ultra-homogenization ultra-sonication strategies and validated by UV-visible spectroscopy analysis that confirms presences of griseofulvin and Zn-NPs peaks at 265 and 360 nm, respectively. The GF-Zn-NHE has mean distribution size 50 nm and zeta potential in the range from -40 to -36 mV with no significant changes in size distribution and particle size within 120 day ageing. Fourier transform infrared spectroscopy spectrum confirmed the presence of griseofulvin and Zn-NPs stretching vibration peaks. Gamma ray has a negative influence on GF-Zn-NE production and stability. GF-Zn-NHE drug release 95% up to 24 h and 98% up to 72 h of GF was observed and Zinc 90% up to 24 h and 95% up to 72 h, respectively. High antimicrobial activity was observed with GF-Zn-NHE against dermatophytic pathogens in compare with GF, GF-NE, zinc nitrate and ketoconazole with inhibition zone ranged from 14 to 36 mm. The results have shown that the MIC value for Cryptococcus neoformans, Prophyromonas gingivalis and Pseudomonas aeruginosa is 0.125 mg ml -1 and for Trichophyton rubrum, L. bulgaricus and Escherichia coli value is 0.25 mg ml -1 and for Candida albicans, Malassezia furfur and Enterococcus faecalis is 0.5 mg ml -1 and finally 1 mg ml -1 for Streptococcus mutans. TEM of treated Cryptococcus neoformans cells with GF-Zn-NHE displayed essentially modified morphology, degradation, damage of organelles, vacuoles and other structures.

Implications of Low-concentration Polymer on the Physical Stability of Glassy Griseofulvin: Role of the Segmental Mobility.

Crystallization of amorphous pharmaceutical solids are widely reported to be affected by the addition of polymer, while the underlying mechanism require deep study. Herein, crystal growth behaviors of glassy griseofulvin (GSF) doped with various 1% w/w polymer were systematically studied. From the molecular structure, GSF cannot form the hydrogen bonding interactions with the selected polymer poly(vinyl acetate), polyvinyl pyrrolidone (PVP), 60:40 vinyl pyrrolidone-vinyl acetate copolymer (PVP/VA 64), and poly(ethylene oxide) (PEO). 1% w/w polymer exhibited weak or no detectable effects on the glass transition temperature (Tg) of GSF. However, crystal growth rates of GSF was altered from 4.27-fold increase to 2.57-fold decrease at 8 ℃ below Tg of GSF. Interestingly, the ability to accelerate and inhibit the growth rates of GSF crystals correlated well with Tg of polymer, indicating the controlling role of segmental mobility of polymer. Moreover, ring-banded growth of GSF was observed in the polymer-doped systems. Normal compact bulk and ring-banded crystals of GSF were both characterized as the thermodynamically stable form I. More importantly, formation of ring-banded crystals of GSF can significantly weaken the inhibitory effects of polymer on the crystallization of glassy GSF.

Accelerated stability modeling of recrystallization from amorphous solid Dispersions: A Griseofulvin/HPMC-AS case study.

Amorphous solid dispersions (ASDs) represent an important approach for enhancing oral bioavailability for poorly water soluble compounds; however, assuring that these ASDs do not recrystallize to a significant extent during storage can be time-consuming. Therefore, various efforts have been undertaken to predict ASD crystallization levels with kinetic models. However, only limited success has been achieved due to limits on crystal content quantification methods and the complexity of crystallization kinetics. To increase the prediction accuracy, the accelerated stability assessment program (ASAP), employing isoconversion (time to hit a specification limit) and a modified Arrhenius approach, are employed here for predictive shelf-life modeling. In the current study, a model ASD was prepared by spray drying griseofulvin and HPMC-AS-LF. This ASD was stressed under a designed combinations of temperature, relative humidity and time with the conditions set to ensure stressing was carried out below the glass transition temperature (Tg) of the ASD. Crystal content quantification method by X-ray powder diffraction (XRPD) with sufficient sensitivity was developed and employed for stressed ASD. Crystallization modeling of the griseofulvin ASD using ASAPprime® demonstrated good agreement with long-term (40 °C/75 %RH) crystallinity levels and support the use of this type of accelerated stability studies for further improving ASD shelf-life prediction accuracy.

Synthesis and Antifungal Activities of Novel Griseofulvin Derivatives as Potential Anti-Phytopathogenic Fungi Agents.

The extensive and repeated application of chemical fungicides results in the rapid development of fungicide resistance. Novel antifungal pesticides are urgently required. Natural products have been considered precious sources of pesticides. It is necessary to discover antifungal pesticides by using natural products. Herein, 42 various griseofulvin derivatives were synthesized. Their antifungal activities were evaluated in vitro. Most of them showed good antifungal activity, especially 3d exhibited a very broad antifungal spectrum and the most significant activities against 7 phytopathogenic fungi. In vivo activity results suggested that 3d protected apples and tomatoes from serious infection by phytopathogenic fungi. These proved that 3d had the potential to be a natural product-derived antiphytopathogenic fungi agent. Furthermore, docking analysis suggested that tubulin might be one of the action sites of 3d. It is reasonable to believe that griseofulvin derivatives are worth further development for the discovery of new pesticides.

Phase Identification and Discovery of an Elusive Polymorph of Drug-Polymer Inclusion Complex Using Automated 3D Electron Diffraction.

3D electron diffraction (3D ED) has shown great potential in crystal structure determination in materials, small organic molecules, and macromolecules. In this work, an automated, low-dose and low-bias 3D ED protocol has been implemented to identify six phases from a multiple-phase melt-crystallisation product of an active pharmaceutical ingredient, griseofulvin (GSF). Batch data collection under low-dose conditions using a widely available commercial software was combined with automated data analysis to collect and process over 230 datasets in three days. Accurate unit cell parameters obtained from 3D ED data allowed direct phase identification of GSF Forms III, I and the known GSF inclusion complex (IC) with polyethylene glycol (PEG) (GSF-PEG IC-I), as well as three minor phases, namely GSF Forms II, V and an elusive new phase, GSF-PEG IC-II. Their structures were then directly determined by 3D ED. Furthermore, we reveal how the stabilities of the two GSF-PEG IC polymorphs are closely related to their crystal structures. These results demonstrate the power of automated 3D ED for accurate phase identification and direct structure determination of complex, beam-sensitive crystallisation products, which is significant for drug development where solid form screening is crucial for the overall efficacy of the drug product.

Development and characterization of co-amorphous griseofulvin/L-leucin by modified solvent processing hot-melt extrusion.

Co-amorphous systems (CAMS) were developed between griseofulvin (GRI) and L-leucine (LEU) at 2:1 wt ratio, by application of a novel solvent assisted hot-melt extrusion (HME) method that involved wet processing/drying of the feeds prior to extrusion. CAMS formation was confirmed by powder crystallography (pXRD) and thermal analysis (DSC). Intermolecular H-bonding between the carbonyl groups of GRI and the hydroxyl and amino groups of LEU were identified by vibrational spectroscopy (ATR-FTIR). The measured glass transition temperatures (Tg) of the extrudates from feeds processed with aqueous acetic acid (AcOH) were markedly lower than that of neat amorphous GRI and values predicted from Gordon-Taylor equation, indicating plasticizing action of AcOH. Drug concentrations during dissolution of CAMS under non-sink conditions (Sink Index 0.0115) were up to x82 higher at plateau compared to crystalline drug solubility. The degree of supersaturation lasted for at least 24 h. Plasticizer (Compritol®/Kolliphor® 75/25) added before extrusion did not impact significantly on CAMS formation but altered the dissolution profile from a spring-and-parachute profile to gradual rise to maximum. These findings reinforce the application of drug/amino acid-based CAMS in formulation, particularly for high-dose drugs, for which polymers are unsuited due to the required large proportions.

Microwave Synthesis of Nanostructured Functionalized Polylactic Acid (nfPLA) for Incorporation Into a Drug Crystals to Enhance Their Dissolution.

Active pharmaceutical ingredients that have low aqueous solubility pose a challenge in the field of drug delivery. In this paper we report for the first time the synthesis of nano-structured, hydrophilized polylactic acid (nfPLA) and its application in the delivery of low solubility drugs. Microwave induced acid oxidation was used to generate nfPLA where the oxygen concentration increased from 27.0 percent to 41.0 percent. Also, the original non dispersible PLA was converted to a relatively dispersible form with an average particle size of 131.4 nm and a zeta potential of -23.3 mV. Small quantities of the nfPLA were incorporated into the crystals (0.5 to 2.0 % by weight) of a highly hydrophobic, low solubility antifungal drug Griseofulvin (GF) to form a composite (GF-nfPLA). An antisolvent approach was used for the synthesis of the drug composite. SEM and Raman imaging showed non-uniform distribution of the nfPLA on the crystal surface. The solubility of GF increased from 8.89 µg/mL to as high as 49.67 µg/mL for the GF-nfPLA. At the same time zeta potential changed from -15.4 mV to -39.0 mV, therefore the latter was a relatively stable colloid. Octanol-water partitioning also showed a similar effect as logP reduced from 2.16 for pure GF to 0.55 for GF-nfPLA. In vitro dissolution testing showed six times higher aqueous solubility of GF-nfPLA compared to pure GF. The time for 50 (T50) and 80 % (T80) dissolution reduced significantly for the nfPLA composites; T50 reduced from 40.0 to 14.0 min and T80 reduced form unachievable to 47.0 min. Overall, the PLA which is an FDA approved, bioabsorbable polymer can be used to enhance the dissolution of hydrophobic pharmaceuticals and this can lead to higher efficacy and lower the required dosage for drugs.

Integrated Transcriptome and Proteome Analysis Reveals that the Antimicrobial Griseofulvin Targets Didymella segeticola Beta-Tubulin to Control Tea Leaf Spot.

Because effective control measures are lacking, tea leaf spot caused by Didymella segeticola results in huge tea (Camellia sinensis) production losses on tea plantations in Guizhou Province, southwestern China. Screening for natural antimicrobial agents with higher control effects against this pathogen and studying their modes of action may contribute to disease management. Here, Penicillium griseofulvum-derived antimicrobial griseofulvin (GSF) can inhibit the hyphal growth of D. segeticola strain GZSQ-4, with a half-maximal effective concentration of 0.37 µg/ml in vitro and a higher curative efficacy at a lower dose of 25 µg/ml for detached tea twigs. GSF induces deformed and slightly curly hyphae with enlarged ends, with protoplasts agglutinated in the hyphae, and higher numbers of hyphal protuberances. GSF alters hyphal morphology and the subcellular structure's order. The integrated transcriptome and proteome data revealed that the transport of materials in cells, cellular movement, and mitosis were modulated by GSF. Molecular docking indicated that beta-tubulin was the most potent target of GSF, with a binding free energy of -13.59 kcal/mol, and microscale thermophoresis indicated that the dissociation constant (Kd) value of GSF binding to beta-tubulin 1, compared with beta-tubulin 2, was significantly lower. Thus, GSF potentially targets beta-tubulin 1 to disturb the chromosomal separation and fungal mitosis, thereby inhibiting hyphal growth.

Modeling of Particle Dissolution Behavior Using a Geometrical Phase-Field Approach.

Material dissolution is a critical attribute of many products in a wide variety of industries. The idealized view of dissolution through established prediction tools should be reconsidered because the number of new substances with low aqueous solubility is increasing. Due to this, a fundamental understanding of the dissolution process is desired. The aim of this study was to develop a tool to predict crystal dissolution performance based on experimentally measurable physical parameters. A numerical simulation, called the phase-field method, was used to simultaneously solve the time evolution of the phase and concentration fields of dissolving particles. This approach applies to diffusion-limited as well as surface reaction-limited systems. The numerical results were compared to analytical solutions, and the influence of particle shape and interparticle proximity on the dissolution process was numerically investigated. Dissolution behaviors of two different substances were modeled. A diffusion-limited model compound, xylitol, with a high aqueous solubility and a surface reaction-limited model compound, griseofulvin, with a low aqueous solubility were chosen. The results of the simulations demonstrated that phase-field modeling is a powerful approach for predicting the dissolution behaviors of pure crystalline substances.

Natural product fragment combination to performance-diverse pseudo-natural products.

Natural product structure and fragment-based compound development inspire pseudo-natural product design through different combinations of a given natural product fragment set to compound classes expected to be chemically and biologically diverse. We describe the synthetic combination of the fragment-sized natural products quinine, quinidine, sinomenine, and griseofulvin with chromanone or indole-containing fragments to provide a 244-member pseudo-natural product collection. Cheminformatic analyses reveal that the resulting eight pseudo-natural product classes are chemically diverse and share both drug- and natural product-like properties. Unbiased biological evaluation by cell painting demonstrates that bioactivity of pseudo-natural products, guiding natural products, and fragments differ and that combination of different fragments dominates establishment of unique bioactivity. Identification of phenotypic fragment dominance enables design of compound classes with correctly predicted bioactivity. The results demonstrate that fusion of natural product fragments in different combinations and arrangements can provide chemically and biologically diverse pseudo-natural product classes for wider exploration of biologically relevant chemical space.

Biodegradable nanoparticles from prosopisylated cellulose as a platform for enhanced oral bioavailability of poorly water-soluble drugs.

Bio-inspired nanotechnology-based strategies are potential platforms for enhanced dissolution and oral biovailability of poorly water-soluble drugs. In this study, a recently patented green biopolymer (Prosopis africana gum, PG) was compatibilized with microcrystalline cellulose (MCC), a conventional polysaccharide, via thermo-regulated coacervation to obtain PG-MCC (1:0, 1:1, 1:2, 2:1, and 0:1) rational blends and the nanoparticles developed with optimized (1:1) biocomposites (termed "prosopisylated cellulose") by combined homogenization-nanoprecipitation technique was engineered as a high circulating system for improved oral bioavailability of griseofulvin (GF), a model Biopharmaceutics Classification System (BCS) Class-II drug. The effects of biopolymer interaction on morphological and microstructural properties of drug-free biocomposites obtained were investigated by Fourier transform infra-red spectroscopy, scanning electron microscopy and x-ray diffractometry, while the physicochemical properties and in-vivo pharmacokinetics of GF-loaded nanoparticles were also ascertained. Optimized biocomposites revealed inter-molecular and intra-molecular hydrogen bonding between the hydroxyl group of MCC and polar components of PG, as well as reduction in crystallinity of MCC. Griseofulvin-loaded nanoparticles were stable, displayed particles with relatively smooth surfaces and average size of 26.18 ± 0.94 . nm, with zeta potential and polydispersity index of 32.1 ± 0.57 mV and 0.173 ± 0.06, respectively. Additionally, the nanoparticles showed good entrapment efficiency (86.51 ± 0.93 %), and marked improvement in griseofulvin dissolution when compared to free drug, with significantly (p < 0.05) higher GF release in basic than acidic PEG-reinforced simulated bio-microenvironments. Besides, x-ray diffractogram of GF-loaded nanoparticles showed amorphization with few characteristic peaks of GF while infra-red spectrum indicated broader principal peaks of GF and components compatibility. Furthermore, GF-loaded nanoparticles showed low plasma clearance with three-fold increase in systemic bioavailability of griseofulvin compared with free drug. These results showed that prosopisylated cellulose nanoparticles would be a facile approach to improve oral bioavailability of BCS class-II drugs and can be pursued as a new versatile drug delivery platform.

Melt milling as manufacturing method for solid crystalline suspensions.

Production of submicron particles (0.1-1 µm) has been identified by the pharmaceutical industry as a key technology to enhance the bioavailability of poorly water-soluble drugs. However, nanosuspensions derived from commonly applied wet milling suffer from long-term stability issues, making further downstream processing necessary. In previous works, the formulation as a long-term stable solid crystalline suspension (SCS) was introduced, for which the crystalline drug is ground in a (molten) hydrophilic carrier matrix. The model formulation of the antimycotic Griseofulvin and the sugar alcohol Xylitol was reused for comparative purposes. Due to process limitations regarding the degree of comminution, the present work demonstrates the application of fine grinding in the framework of SCS manufacturing. A custom-built mill with annular gap geometry successfully yielded particles in the targeted submicron range. A process optimization study lead to improved energy utilization during grinding, which reduced the necessary grinding time and, thereby, the thermal exposition of the drug. Investigation of solid-state properties of the SCS, via differential scanning calorimetry and x-ray powder diffraction, showed no alteration even for extended grinding times. In dissolution experiments, the melt-milled SCS outperformed its predecessors, although mostly agglomerates were found by SEM imaging in the solidified product. In conclusion, melt milling is a valuable tool to overcome low aqueous solubility.

A general method for cultivating single crystals from melt microdroplets.

The cultivation of single crystals from solution is usually a time-consuming trial-and-error process. Here, we report a general strategy for rapidly cultivating single crystals from melt microdroplets within tens of minutes at the microgram scale. This strategy was successfully applied to the important polymorphic system griseofulvin to provide missing structural information of Form III, for which single crystals could not be cultivated from solution, as well as to twenty clinical drugs to verify its generality.

Impact of media material and process parameters on breakage kinetics-energy consumption during wet media milling of drugs.

While crosslinked polystyrene (CPS) beads and yttrium-stabilized zirconia (YSZ) beads have been commonly used as media for wet milling of poorly soluble drugs and their dissolution enhancement, no first-principle rationale exists for selecting the bead material. The aim of this study is to investigate the impact of stirrer speed (2000-4000 rpm) and CPS bead loading (~20-60%) on the breakage kinetics-energy consumption during milling of griseofulvin, a model poorly soluble drug, and compare the performance of CPS vs. YSZ at the highest bead loading. Laser diffraction, SEM, rheological analysis, and XRPD were used for characterization. The milling was most effective at the highest bead loading-stirrer speed. A microhydrodynamic model suggests that an increase in stirrer speed led to faster breakage due to more frequent and forceful CPS bead-bead collisions. Despite causing slight decrease in maximum contact pressure, an increase in CPS bead loading caused a dramatic increase in average frequency of drug particle compressions, which dominated the faster breakage observed. While YSZ generally required higher specific energy consumption than CPS, it achieved the same product fineness faster than CPS. The microhydrodynamic model rationalized the favorable use of YSZ over CPS beads within the experimental domain studied.

Solubility of Pharmaceutical Ingredients in Natural Edible Oils.

Natural edible oils (NEOs) are common excipients for lipid-based formulations. Many of them are complex mixtures comprising hundreds of different triglycerides (TGs). One major challenge in developing lipid-based formulations is the variety in NEO compositions affecting the solubility of active pharmaceutical ingredients. In this work, solubilities of indomethacin (IND), ibuprofen (IBU), and fenofibrate (FFB) in soybean oil and in coconut oil were measured via differential scanning calorimetry, high-performance liquid chromatography, and Raman spectroscopy. Furthermore, this work proposes an approach that mimics NEOs using one key TG and models the API solubilities in these NEOs based on perturbed-chain statistical associating fluid theory (PC-SAFT). Key TGs were determined using the 1,2,3-random hypothesis, and PC-SAFT parameters were estimated via a group-contribution method. Using the proposed approach, the solubility of IBU and FFB was modeled in soybean oil and coconut oil. Furthermore, the solubilities of five more APIs (IND, cinnarizine, naproxen, griseofulvin, and felodipine) were modeled in soybean oil. All modeling results were found in very good agreement with the experimental data. The influence of different NEO kinds on API solubility was examined by comparing FFB and IBU solubilities in soybean oil and refined coconut oil. PC-SAFT was thus found to allow assessing the batch-to-batch consistency of NEO batches in silico.

Synergistic and antagonistic effects of various amphiphilic polymer combinations in enhancing griseofulvin release from ternary amorphous solid dispersions.

We aimed to elucidate the impact of various amphiphilic polymers on drug wettability and recrystallization inhibition and in turn drug release from binary and ternary amorphous solid dispersions (ASDs). Griseofulvin (GF) was selected as a challenging, fast-crystallizing poorly soluble drug. GF solutions with hydroxypropyl cellulose (HPC), Kollidon VA64 (VA64), and Soluplus® (Sol) were spray-dried to prepare various binary and ternary GF ASDs. XRPD, DSC, and Raman spectroscopy confirmed the formation of ASDs and suggested that HPC appears to have lower miscibility and weaker interactions with GF than Sol/VA64 with GF. In dissolution tests, the Sol-based ASD generated supersaturation very slowly and achieved 170% GF supersaturation in 210 min (230% after 6 h). The HPC-based ASD exhibited fast recrystallization in the matrix due to its low glass transition temperature and poor miscibility of HPC with GF; whereas VA64-based ASD exhibited 220% supersaturation in 10 min followed by rapid GF recrystallization. The modified Washburn experiments revealed significant wettability enhancement of GF by HPC/VA64 and inadequate enhancement by Sol, which explains the initial rapid release from VA64-based ASD and slow supersaturation build-up in Sol-based ASD. Poor GF recrystallization inhibition ability of the HPC/VA64 was confirmed by desupersaturation tests and polarized light microscope imaging. Addition of HPC to Sol and VA64 deteriorated the GF release from the ASDs with either Sol or VA64 alone. In most cases, combination of Sol with HPC/VA64 led to a trade-off between high supersaturation and rapid drug release. A strong synergistic effect emerged for the ASD with 5:1 Sol:VA64: ~220% supersaturation within 30 min was generated and maintained over three hours, whereas an antagonistic effect was observed for 1:5 Sol:VA64 with 70% supersaturation. The combination of an amphiphilic polymer that provides effective drug wettability enhancement (VA64) as a minor component along with an amphiphilic crystallization inhibiting polymer as a major component (Sol), which also provides micellar solubilization of the drug, in a ternary ASD exhibited synergistic rapid drug release with prolonged supersaturation.

Stability of Azathioprine, Clonidine Hydrochloride, Clopidogrel Bisulfate, Ethambutol Hydrochloride, Griseofulvin, Hydralazine Hydrochloride, Nitrofurantoin, and Thioguanine Oral Suspensions Compounded with SyrSpend SF pH4.

To allow for tailored dosing and overcome swallowing difficulties, compounded liquid medication is often required in pediatric patients. The objective of this study was to evaluate the stability of oral suspensions compounded with SyrSpend SF PH4 and the commonly used active pharmaceutical ingredients azathioprine (powder) 50 mg/mL, azathioprine (from tablets) 50 mg/mL, clonidine hydrochloride (powder) 0.1 mg/mL, clopidogrel bisulfate (from tablets) 5 mg/mL, ethambutol hydrochloride (powder) 50 mg/mL, ethambutol hydrochloride (from tablets) 50 mg/mL, ethambutol hydrochloride (powder) 100 mg/mL, griseofulvin (powder) 25 mg/mL, hydralazine hydrochloride (powder) 4 mg/mL, nitrofurantoin (powder) 10 mg/mL, and thioguanine (powder) 2.5 mg/mL. Suspensions were compounded at the concentrations listed above and stored at controlled room and refrigerated temperatures. Stability was assessed by measuring the percentage recovery at 0 day (baseline), and at 7 days, 14 days, 30 days, 60 days, and 90 days. Active pharmaceutical ingredients quantification was performed by high-performance liquid chromatography, via a stability-indicating method. The following oral suspensions compounded using SyrSpend SF PH4 as the vehicle showed a beyond-use date of 90 days when stored both at room or refrigerated temperatures: clonidine hydrochloride 0.1 mg/mL, ethambutol hydrochloride 50 mg/mL and 100 mg/mL, griseofulvin 25 mg/mL, nitrofurantoin 10 mg/mL, and thioguanine 2.5 mg/mL, all compounded from the active pharmaceutical ingredients in powder form. Suspensions compounded using the active pharmaceutical ingredients from tablets presented a lower beyond-use date: 30 days for ethambutol hydrochloride 50 mg/mL and hydralazine hydrochloride 4 mg/mL, stored at both temperatures, and for clopidogrel bisulfate 5 mg/mL when stored only at refrigerated temperature. Azathioprine suspensions showed a beyond-use date of 14 days when compounded using active pharmaceutical ingredients in powder form at both temperatures. This suggests that SyrSpend SF PH4 is suitable for compounding active pharmaceutical ingredients from different pharmacological classes.

Preparation and Characterization of Griseofulvin Solid Dispersions.

Amorphous solid dispersion (SD) technique has been used for improving the solubility and bioavailability of poorly water-soluble compounds. However, the stability of these SD is a concern due to the high propensity of metastable amorphous form to convert into its stable crystalline form. In this study, the stability of SD of griseofulvin (GSV), a high crystallization tendency compound, was evaluated in the presence of commonly used Food and Drug Administration-approved hydrophilic polymers such as polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose, Eudragits, and polyethylene glycol. Physical mixtures (PM) and SD were prepared at various drug to polymer ratios (3:1, 1:1, 1:2, 1:9 w/w) using the solvent evaporation technique. PM and SD were characterized by powder X-ray diffractometer and modulated differential scanning calorimetry to confirm the formation of amorphous dispersions and to understand the crystallization inhibition effectiveness of polymers. Infrared (IR), Raman spectroscopy, and molecular modeling were used to understand the role of interaction between GSV and polymers for stabilization of dispersions. We observed that most polymers are ineffective in stabilizing the amorphous form of GSV at low concentrations, that is, 3:1, 1:1, and 1:2 w/w except for PVP K-90, which was effective at a concentration of 1:1 w/w. Slight peak shifts were observed in IR and Raman; however, these shifts were inconclusive of molecular interactions between GSV and hydrophilic polymers. GSV's high crystallization tendency coupled with a lack of hydrogen bond acceptors/donors hinders the formation of stable SD, and thus, a higher polymer concentration is a prerequisite for their long-term stability.

Direct incorporation of nano graphene oxide (nGO) into hydrophobic drug crystals for enhanced aqueous dissolution.

This paper reports the development of a successful anti-solvent method that incorporates colloidal nano scale graphene oxide (nGO) directly into hydrophobic drug crystals. The nGO dispersed in solution acted as nucleating sites for crystallization and were embedded into the drug crystals without altering its structure or physical properties such as melting point. Several composites of drugs Sulfamethoxazole and Griseofulvin were synthesized with nGO concentration ranging between 0.2 and 1.0 %. The presence of nGO dramatically enhanced the dissolution rate. The time needed to reach a 50 % release (T50) reduced from 42-14 min with the integration of 0.8 % nGO in SMZ, while in GF the reduction was from 44-27 min with 0.5 % nGO. Increased release rates are attributed to the presence of the hydrophilic nGO which hydrogen bond more so with the aqueous mediums. Therefore, the incorporation of nGO into poorly soluble drugs is an effective approach towards drug delivery and bioavailability improvement and opens a new approach to high performance drug delivery.