Dissolution Assay Research Articles

Organic solvent-free benznidazole nanosuspension as an approach to a novel pediatric formulation for Chagas disease.

Aim: Benznidazole (BNZ), a class-II drug, is the primary treatment for Chagas disease, but its low aqueous solubility presents challenges in formulation and efficacy. Nanosuspensions (NS) could potentially address these issues.Methods: BNZ-NS were prepared using a simple, organic solvents-free nano-milling approach. Physicochemical characterizations were conducted on both NS and lyophilized solid-state BNZ-nanocrystals (NC).Results: BNZ-NS exhibited particle size <500nm, an acceptable polydispersity index (0.23), high Z-potential, and physical stability for at least 90days. BNZ-NC showed tenfold higher solubility than pure BNZ. Dissolution assays revealed rapid BNZ-NS dissolution. BNZ-NC demonstrated biocompatibility on an eukaryotic cell and enhanced BNZ efficacy against trypomastigotes of Trypanosoma cruzi.Conclusion: BNZ-NS offers a promising alternative, overcoming limitations associated with BNZ for optimized pharmacotherapy.

Bioequivalence prediction with small-scale biphasic dissolution and simultaneous dissolution-permeation apparatus—An aripiprazole case study

Both biphasic dissolution and simultaneous dissolution-permeation (D-P) systems have great potential to improve the in vitro-in vivo correlation compared to simple dissolution assays, but the assay conditions, and the evaluation methods still need to be refined in order to effectively use these apparatuses in drug development.Therefore, this comprehensive study aimed to compare the predictive accuracy of small-volume (16–20 mL) D-P system and small-volume (40–80 mL) biphasic dissolution apparatus in bioequivalence prediction of five aripiprazole (ARP) containing marketed drug products.Assay conditions, specifically dose dependence were studied to overcome the limitations of both small-scale systems. In case of biphasic dissolution the in vivo maximum plasma concentration (Cmax) prediction greatly improved with the dose reduction of ARP, while in case of the D-P setup the use of whole tablet gave just as accurate prediction as the scaled dose. With the dose reduction strategy both equipment was able to reach 100 % accuracy in bioequivalence prediction for Cmax ratio. In case of the in vivo area under the curve (AUC) prediction the predictive accuracy for the AUC ratio was not dependent on the dose, and both apparatus had a 100 % accuracy predicting bioequivalence based on AUC results.This paper presents for the first time that not only selected parameters of flux assays (like permeability, initial flux, AUC value) were used as an input parameter of a mechanistic model (gastrointestinal unified theory) to predict absorption rate but the whole in vitro flux profile was used. All fraction absorbed values estimated by Predictor Software fell within the ±15 % acceptance range during the comparison with the in vivo data.

The baicalein amorphous solid dispersion to enhance the dissolution and bioavailability and effects on growth performance, meat quality, antioxidant capacity and intestinal flora in Taihang chickens

Baicalein (BAI) is a natural flavonoid with antioxidant, antitumor and antibacterial properties. However, the bioavailability of BAI was limited due to low solubility. This study aims to improve the solubility of BAI through the amorphous solid dispersion (ASD) and evaluate changes in its pharmacokinetics and pharmacodynamics in Taihang chickens. Polyethylene caprolactam-polyvinyl acetate-polyethylene glycol grafted copolymer (Soluplus) was chosen as the carrier, and ASD was prepared by rotary evaporation and was characterized by powder X-ray diffractions (PXRD), differential scanning calorimetry (DSC) and fourier transform infrared spectroscopy (FT-IR). In vitro dissolution assays were used to screen the optimal ratio of drug to carrier, in vivo pharmacokinetic assays were conducted to investigate the promoting effect on the absorption. In addition, the effects of ASD on the growth performance, meat quality, antioxidant capacity and intestinal flora were investigated. ASD (1:9 and 2:8) did not exhibit crystal diffraction peaks of BAI in PXRD or endothermic peaks in DSC, indicating the successful preparation of ASD. The results of in vitro dissolution assay showed that the cumulative dissolution rate of ASD (2:8) within 600 min was 52.67%, which was 7.84-fold higher than BAI. The pharmacokinetic results showed that the peak concentration (Cmax) and the area under the drug-time curve (AUC0∼24) of ASD (2:8) was (5.20 ± 0.82) μg/mL and (17.03 ± 0.67) μg·h/mL, which was 1.91 and 2.64-fold higher than BAI, respectively. Dietary supplementation of BAI and ASD could increase average daily gain (ADG), while decrease feed conversion ratio (FCR), but there was no significant difference (P > 0.05). The drip loss of BAIASD group was lower than BAI group (P < 0.05). In addition, the antioxidant capacity of Taihang chickens were enhanced, the diversity and the abundance of beneficial bacteria was improved. Results of BAI upon the dietary supplementation tested in Taihang chickens, after preparation of ASD, indicating a superior enhancement effect in growth performance, meat quality, antioxidant capacity and intestinal flora due to an improved solubility and optimized bioavailability.

Impact of crystal polymorphism of rifaximin on dissolution behavior

IntroductionRifaximin is an intestinal antiseptic which has five (pseudo) polymorphs α, β, γ, δ and ε. These last (pseudo)polymorphs have different physicochemical properties. The objective of the study is to assess the impact of rifaximin polymorphism on its dissolution rate which could affect its bioavailability. Material and methodsThe analytical validation of dissolution assay method by UV–Visible spectrophotometry was carried out according to ICH Q2. The physicochemical characterization (solubility test, FTIR, DSC, XRD) was carried out on four active pharmaceutical ingredient (MP1, MP2, MP3, MP4). MP1 and MP2 were used by the manufacturer of generic brand 1 (G1) and MP3 and MP4 were used by the manufacturer of generic brand 2 (G2). The comparative in-vitro dissolution study was carried out on the leader brand (P), G1 and G2. ResultsThe four MPs were analyzed by XRD. The results of analysis showed that MP1 and MP4 were a mixture of α form and amorphous form. MP2 had an amorphous form and MP3 had a crystalline form β. The spectra of FTIR showed that the four MP had characteristics bands of rifaximin in the domain 4000-400 cm−1. The differences between the spectra of the four MPs were observed among the amorphous form (MP2), around the region 1800 to 1820 cm−1 which is attributed to the vibration of the CO group. An additional difference observed among the amorphous form (MP2) is around the region 1400 cm−1 which is attributed to the banding OH. The thermograms of MP1, MP2 and MP4 showed endothermic peaks which are probably attributed to the departure of water which indicate that MP1, MP2 and MP4 are pseudopolymoph (hydrate). For the four MPs, probably the melting points are interrupted by the phenomenon of phase transformations (Crystallization) which are reflected by exothermic peaks around 200°C–250 °C.Our results showed that the crystalline polymorphism of rifaximin influences its solubility. According to the results of the solubility test, the β crystal form of rifaximin (MP3) had the lowest solubility (3.47 μg/ml). MP2 had the highest solubility (8.35 μg/ml) and MP1 and MP4 had intermediate solubilities (5.47 μg/ml and 6.74 μg/ml). Comparative in vitro dissolution results showed that the dissolution profile of P was not similar to that of G1 and G2 (% dissolution (P)30min = 60%; % dissolution (G1) 30 min = 100% and % dissolution (G2) 30 min = 115%; f1(P versus G1) = 44; f1(P versus G2) = 61) in M1, while G1 and G2 had comparatively similar dissolution profiles (% dissolution (G1) 30 min = 100%; % dissolution (G1) 30 min = 110%; f1 (G1 versus G2) = 14) in M1. ConclusionThis study highlighted the impact of rifaximin polymorphism on its physico-chemical properties (crystal structure, thermal behavior, solubility) and on its dissolution behavior which could affect the rifaximin bioavailability.

The non-ribosomal peptide synthetase-independent siderophore (NIS) rhizobactin produced by Caballeronia mineralivorans PML1(12) confers the ability to weather minerals.

To mobilize nutrients entrapped into minerals and rocks, heterotrophic bacteria living in nutrient-poor environments have developed different mechanisms based mainly on acidolysis and chelation. However, the genetic bases of these mechanisms remain unidentified. To fill this gap, we considered the model strain Caballeronia mineralivorans PML1(12) known to be effective at weathering. Based on its transcriptomics and proteomics responses in Fe-depleted conditions, we pointed a cluster of genes differentially expressed and putatively involved in the production of siderophores. In this study, we report the characterization of this gene region coding for the production of a non-ribosomal peptide synthetase-independent siderophore (NIS). Targeted mutagenesis associated with functional assays and liquid chromatography coupled to high-resolution tandem mass spectrometry demonstrated the production of a single siderophore, identified as rhizobactin. This siderophore represents the first NIS containing malic acid in its structure. The evidence for the implication of rhizobactin in mineral weathering was demonstrated during a hematite dissolution assay. This study provides the first demonstration of the synthesis of a NIS in the genus Caballeronia and its involvement in mineral weathering. Our conclusions reinforce the idea that strain PML1(12) is particularly well adapted to nutrient-poor environments. IMPORTANCE This work deciphers the molecular and genetic bases used by strain PML1(12) of Caballeronia mineralivorans to mobilize iron and weather minerals. Through the combination of bioinformatics, chemical, and phylogenetic analyses, we characterized the siderophore produced by strain PML1(12) and the related genes. This siderophore was identified as rhizobactin and classified as a non-ribosomal peptide synthetase-independent siderophore (NIS). Contrary to the previously identified NIS synthetases that form siderophores containing citric acid, α-ketoglutarate, or succinic acid, our analyses revealed that rhizobactin contains malic acid in its structure, representing, therefore, the first identified NIS with such an acid and probably a new NIS category. Last, this work demonstrates for the first time the effectiveness at weathering minerals of a siderophore of the NIS family. Our findings offer relevant information for different fields of research, such as environmental genomics, microbiology, chemistry, and soil sciences.

Formulation and Characterization of Ursodeoxycholic Acid Nanosuspension Based on Bottom-Up Technology and Box-Behnken Design Optimization.

Ursodeoxycholic acid (UDCA) is a therapeutic agent used for the treatment of cholestatic hepatobiliary diseases in pediatric patients. It is a bile acid that presents high lipophilicity, and it belongs to Class II of the Biopharmaceutical Classification System (BCS), which exhibits low water solubility and high intestinal permeability, which leads to poor oral absorption. The objective of this work was to design and optimize UDCA nanosuspensions by means of the precipitation-ultrasonication method to improve the solubility, dissolution, and oral bioavailability of UDCA. A three-level, three-factor Box-Behnken design was used to optimize formulation variables and obtain uniform, small-particle-size UDCA nanosuspensions. The independent variables were: stabilizer percentage (X1), amplitude (X2), and sonication time (X3), and the dependent variable was the particle size (Y1). In the precipitation-ultrasonication method, UDCA was dissolved in acetone:PEG 400 (1:1 v/v) and quickly incorporated into the antisolvent (pre-cooled aqueous dispersion of HPMC E-15 0.3%), by means of intense sonication at 50 W for 5 min, controlling temperature through an ice water bath. The lyophilization efficacy was evaluated by means of a cryoprotective efficacy test, working with 10% maltose at -80 °C. The nanosuspensions were characterized by dynamic light scattering (DLS), X-ray diffraction, and scanning electron microscopy (SEM). The physicochemical stability was determined at 25 °C and 4 °C at 7, 14, 30, and 60 days, and the UDCA content was analyzed via HPLC-UV. An in vitro dissolution assay and an oral bioavailability study were performed in male Wistar rats. A significant impact was achieved in the optimized nanosuspension with 0.3% (stabilizer), 50 W (amplitude), and 5 min (sonication time), with a particle size of 352.4 nm, PDI of 0.11, and zeta potential of -4.30 mV. It presented adequate physicochemical stability throughout the study and the UDCA content was between 90% and 110%. In total, 86% of UDCA was dissolved in the in vitro dissolution test. The relative oral bioavailability was similar without significant statistical differences when comparing the lyophilized nanosuspension and the commercial tablet, the latter presenting a more erratic behavior. The pharmacokinetic parameters of the nanosuspension and the commercial tablet were Tmax (1.0 ± 0.9 h vs. 2.0 ± 0.8 h, respectively), Cmax (0.558 ± 0.118 vs. 0.366 ± 0.113 µM, respectively), ΔCmax (0.309 ± 0.099 vs. 0.232 ± 0.056, respectively), AUC (4.326 ± 0.471 vs. 2.188 ± 0.353 µg/mL.h, respectively, p < 0.02), and IAUC0-24h (2.261 ± 0.187 µg/mL.h vs. 1.924 ± 0.440 µg/mL.h, respectively). The developed nanosuspension presents an appropriate dosage and administration for pediatric patients. On the other hand, it exhibits an adequate absorption and UDCA oral bioavailability.

3D printed composite dressings loaded with human epidermal growth factor for potential chronic wound healing applications

This study formulated and characterized functional properties of 3D printed composite polymer-based film dressings comprising chitosan (CH) crosslinked with genipin (GE) or CH combined with collagen (COL) and loaded with epidermal growth factor (EGF). The films were characterized using texture analyzer (tensile, adhesion), swelling capacity, X-ray diffraction-XRD, Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy-SEM, drug dissolution, and MTT assay using human dermal fibroblasts. FTIR confirmed crosslinking between CH and GE, CH and COL as well as between CH and EGF while XRD showed amorphous matrix of the films. Mucoadhesion studies showed the films’ ability to adhere to a model simulated wound surface. SEM demonstrated a smooth, homogenous surface indicating content uniformity. The swelling was higher for CH-GE than the CH-COL films while the blank films swelled better than the EGF loaded films. EGF was initially released rapidly, reaching 100% in 2 h, subsequent sharp reduction till 5 h followed by sustained release till 72 h, while MTT assay showed greater than 90% cell viability after 48 h, confirming their biocompatibility. EGF loaded films showed higher cell proliferation than blank equivalents. Overall, the results showed the potential of CH based 3D printed films as suitable dressing platforms to deliver EGF directly to chronic wounds.

Holistically assessing the quality consistency of compound liquorice tablets from similarities of both all chemical fingerprints and the integrated dissolution curves by systematically quantified fingerprint method

In recent years, traditional analytical methods have failed to meet the widespread use of multi-component Chinese pharmaceutical formulations. To solve this problem, this study proposed a comprehensive analytical strategy using compound liquorice tablets (CLTs) as an example, both in terms of chemical quality and dissolution curve consistency. Firstly, the peak purity of the two wavelengths was checked using dual-wavelength absorbance coefficient ratio spectra (DARS) to avoid the fingerprint bias caused by peak purity. Secondly, liquid-phase dual-wavelength tandem fingerprint (DWTF) of 38 batches of CLTs was established for the first time. The two analytical methods were also evaluated using the systematically quantified fingerprint method (SQFM), and the 38 batches of samples were classified into two grades with good quality consistency. Quantitative analysis of the five markers of CLTs was performed simultaneously using the standard curve method (SCM) and the quantitative analysis of multiple components by single marker (QAMS). The results showed no significant differences between the two analytical methods (p > 0.5). In addition, the in vitro dissolution of CLTs in two media (pure water and pH = 4.5 medium) was determined by the total UV fingerprint dissolution assay. The similarity of the dissolution curves was also analyzed by combining the f2 factor and the dissolution-systematically quantified fingerprint method (DSQFM). The result showed that most of the samples had f2 > 50 and Pm satisfied the range of 70–130%. Finally, a principal component analysis (PCA) model was developed to combine the evaluation parameters of chemical fingerprint and dissolution curves for comprehensive analysis of the samples. In this study, a chromatographic and dissolution-based quality analysis method was proposed, which effectively overcomes the shortcomings of previous analytical methods and provides a scientific analytical method for the quality control of natural drugs.

Amorphous solid dispersion preparation via coprecipitation improves the dissolution, oral bioavailability, and intestinal health enhancement properties of magnolol

Magnolol (MAG) is a multifunctional plant polyphenol with anti-inflammatory, antibacterial, antioxidant and antitumor properties. In poultry, it has been shown to improve growth performance, antioxidant, immune functions and intestinal health. However, its applications are limited by poor solubility and low oral bioavailability. This study aimed at improving the water solubility of MAG through solid dispersion and investigating its effects in Arbor Acre (AA) broilers. Hydroxypropyl methylcellulose succinic acid (HPMCAS) was used as a carrier to prepare magnolol solid dispersions (MAG-HPMCAS SD) via antisolvent coprecipitation, which were characterized thereafter. Optimal formulation proportions for SD were screened by in vitro dissolution assays, while its effects on improving absorption were investigated via in vivo pharmacokinetic assays. In addition, we evaluated the effects of MAG-HPMCAS SD on growth performance, antioxidant status, and gut microbiota in AA broilers. The powder samples prepared via antisolvent coprecipitation did not exhibit a crystal diffraction peak of MAG in powder X-ray diffractions or melting point peak in differential scanning calorimetry, proving the successful preparation of an amorphous solid dispersion system. The in vitro dissolution assay showed that the cumulative dissolution rate of MAG-HPMCAS(LF) SD (2:8, w/w) was 100%. Pharmacokinetic analyses revealed that the peak concentration (Cmax) of MAG-HPMCAS SD was 5.07 ± 0.73 μg/mL, which was 1.76 times greater than that of MAG. In addition, AUC0-48 and t1/2 of MAG-HPMCAS SD were 40.49 ± 6.29 g·h/mL and 9.15 ± 3.23 h, respectively, which were 2.17 and 2.56 times higher than those of MAG. Supplementation of MAG-HPMCAS SD in AA broilers significantly increased ADG (7-14 d and 15-21 d) and reduced feed conversion ratio (15-21 d) (P < 0.05). Bacterial diversity in the MAG-HPMCAS SD-supplemented group was greater than in the Control and MAG-supplemented group. Supplementation of MAG-HPMCAS SD stimulated the proliferation of beneficial bacteria, such as Lactobacillaceae and Bifidobacteriaceae. In conclusion, the MAG-HPMCAS SD prepared by coprecipitation improved the dissolution rate, the bioavailability of MAG, growth promotion, antioxidant effects and gut health in broilers.

Potential and weak links in the management of tuberculosis by Pakistani private pharmacy staff.

The emergence of MDR-TB is a global threat and an obstacle to the effective control of TB in Pakistan. A lack of proper TB knowledge among the staff in private pharmacies and the sale of compromised quality anti-TB drugs are the main instigators of multidrug-resistant tuberculosis (MDR-TB). Thus, this study was aimed at investigating the quality and storage conditions of fixed-dose combination (FDC) anti-TB drugs along with the awareness of staff working in private pharmacies regarding the identification of potential patients with TB and dispensing the inappropriate treatment regimens contributing to MDR-TB. The study is completed in two phases. In phase I a cross-sectional study is performed using two quantitative research designs, i.e., exploratory and descriptive, to evaluate the knowledge of private pharmacy staff. The sample of 218 pharmacies was selected. While in phase II cross sectional survey is conducted in 10 facilities from where FDC anti TB drugs were sampled for analyzing their quality. Results revealed the presence of pharmacists only at 11.5% of pharmacies. Approximately 81% of staff at pharmacies had no awareness of MDR-TB, while 89% of pharmacies had no TB-related informative materials. The staff identified that most of the patients with TB (70%) were of poor socio-economic class, which restricted their purchase of four FDCs only up to 2-3 months. Only 23% were acquainted with the Pakistan National TB Program (NTP). Except for MDR-TB, the results showed a significant correlation between the experiences of staff with TB awareness. Findings from the quality evaluation of four FDC-TB drugs indicated that the dissolution and content assay of rifampicin were not according to the specifications, and overall, 30% of samples failed to comply with specifications. However, the other quality attributes were within the limits. In light of the data, it can be concluded that private pharmacies could be crucial to the effective management of NTP through the timely identification of patients with TB, appropriate disease and therapy-related education and counseling, and proper storage and stock maintenance.

Grouping of orally ingested silica nanomaterials via use of an integrated approach to testing and assessment to streamline risk assessment

BackgroundNanomaterials can exist in different nanoforms (NFs). Their grouping may be supported by the formulation of hypotheses which can be interrogated via integrated approaches to testing and assessment (IATA). IATAs are decision trees that guide the user through tiered testing strategies (TTS) to collect the required evidence needed to accept or reject a grouping hypothesis. In the present paper, we investigated the applicability of IATAs for ingested NFs using a case study that includes different silicon dioxide, SiO2 NFs. Two oral grouping hypotheses addressing local and systemic toxicity were identified relevant for the grouping of these NFs and verified through the application of oral IATAs. Following different Tier 1 and/or Tier 2 in vitro methods of the TTS (i.e., in vitro dissolution, barrier integrity and inflammation assays), we generated the NF datasets. Furthermore, similarity algorithms (e.g., Bayesian method and Cluster analysis) were utilized to identify similarities among the NFs and establish a provisional group(s). The grouping based on Tier 1 and/or Tier 2 testing was analyzed in relation to available Tier 3 in vivo data in order to verify if the read-across was possible and therefore support a grouping decision.ResultsThe measurement of the dissolution rate of the silica NFs in the oro-gastrointestinal tract and in the lysosome identified them as gradually dissolving and biopersistent NFs. For the local toxicity to intestinal epithelium (e.g. cytotoxicity, membrane integrity and inflammation), the biological results of the gastrointestinal tract models indicate that all of the silica NFs were similar with respect to the lack of local toxicity and, therefore, belong to the same group; in vivo data (although limited) confirmed the lack of local toxicity of NFs. For systemic toxicity, Tier 1 data did not identify similarity across the NFs, with results across different decision nodes being inconsistent in providing homogeneous group(s). Moreover, the available Tier 3 in vivo data were also insufficient to support decisions based upon the obtained in vitro results and relating to the toxicity of the tested NFs.ConclusionsThe information generated by the tested oral IATAs can be effectively used for similarity assessment to support a grouping decision upon the application of a hypothesis related to toxicity in the gastrointestinal tract. The IATAs facilitated a structured data analysis and, by means of the expert’s interpretation, supported read-across with the available in vivo data. The IATAs also supported the users in decision making, for example, reducing the testing when the grouping was well supported by the evidence and/or moving forward to advanced testing (e.g., the use of more suitable cellular models or chronic exposure) to improve the confidence level of the data and obtain more focused information.

Dissolution Assay of Bupropion/Naltrexone Hydrochloride Salts of Bilayer Composition Tablets Following the Development and Validation of a Novel HPLC Method

Compounded medicinal products containing bupropion hydrochloride (BUP·HCl) and naltrexone hydrochloride (NTX·HCl) are available as adjunct therapy for the management of weight in obese/overweight adults. The present work describes the development and validation of a novel RP-HPLC method for a simultaneous quantitation during the dissolution of both drugs from compounded bilayer composition tablets. The method involves a Nucleosil 100-3 C-18 column (4.6 × 150 mm) and a mobile phase of a 70%/30% v/v ACN/KH2PO4·H2O aqueous solution of a 5 mM concentration. The flow rate was set at 1.35 mL/min and the detection was conducted using UV spectrophotometry (λmax 214 nm). The method was validated according to the ICH guidelines and fulfilled the specifications for the specificity, linearity, accuracy, precision and stability for both the sample and standard solutions. Furthermore, the robustness of the method was evaluated by applying a fractional factorial experimental design and by utilizing both graphical and statistical approaches to identify the HPLC factors that should be strictly controlled during the analysis. The method proved to be suitable for the analysis of the dissolution samples and, consequently, the release of BUP·HCl and NTX·HCl from the formulations.

Biophysical Evaluation of Water-Soluble Curcumin Encapsulated in β-Cyclodextrins on Colorectal Cancer Cells.

Curcumin (CUR), a curcuminoid originating from turmeric root, possesses diverse pharmacological applications, including potent anticancer properties. However, the use of this efficacious agent in cancer therapy has been limited due to low water solubility and poor bioavailability. To overcome these problems, a drug delivery system was established as an excipient allowing improved dispersion in aqueous media coupled with enhanced in vitro anticancer effects. Different analyses such as UV-vis spectroscopy, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), solubility and dissolution assays were determined to monitor the successful encapsulation of CUR within the inner cavity of a β-cyclodextrin (β-CD) complex. The results indicated that water solubility was improved by 205.75-fold compared to pure CUR. Based on cytotoxicity data obtained from MTT assays, the inclusion complex exhibited a greater decrease in cancer cell viability compared to pure CUR. Moreover, cancer cell migration rates were decreased by 75.5% and 38.92%, invasion rates were decreased by 37.7% and 35.7%, while apoptosis rates were increased by 26.3% and 14.2%, and both caused caspase 3 activation toward colorectal cancer cells (SW480 and HCT116 cells). This efficacious formulation that enables improved aqueous dispersion is potentially useful and can be extended for various chemotherapeutic applications. Preliminary toxicity evaluation also indicated that its composition can be safely used in humans for cancer therapy.

Development and cytotoxicity evaluation of a cylindrical pH-responsive chitosan-genipin hydrogel for the oral delivery of diclofenac sodium

A cylindrical hydrogel composed of chitosan (1.250 % w/v) and genipin (0.185 % w/v) was developed for the oral delivery of diclofenac sodium (0.250 % w/v). The produced hydrogel was a dosage form with a porous structure and pH-dependent swelling and release profiles. Dissolution studies revealed 10 ± 0.4 % drug release at pH 1.2 after 2 h and 70 ± 13.5 % at pH 6.8 at 5 h. Release at gastric media simulation was 6.1 ± 2.0 % after 2 h at pH 3.0 and 88.2 ± 5.0 % after 2 h at intestinal fluid simulation at pH 7.0. The hydrogel components did not induce in vitro cytotoxic effects in MRC5 and Caco-2 cells at the two lowest concentrations tested by MTT assay. Cellular viability was between 75 ± 5.9 % and 106 ± 3.7 % for individual components and between 71 ± 4.1 % and 106 ± 15.1 % for fractions taken from the dissolution assays. Our findings suggest that the proposed formulation could be a potential candidate for a gastro-resistant drug delivery system of diclofenac sodium.

Poly(1-vinylpyrrolidone-co-vinyl-acetate)-based electrospun dissolvable nanofibrous film for quercetin administration

This study used electrospinning to produce a water-soluble polymeric nanofibrous film incorporated with quercetin. Scanning Electron Microscopy showed that the diameter of the nanofibers decreased from (670 ± 200) nm to (390 ± 90) nm as the amount of quercetin increased from 0% to 15%. The FTIR confirmed the presence of quercetin in the films and suggested the formation of physical interactions between the drug and the polymer. The XRD results confirmed the amorphous character of the nanofibers, and the loss of crystallinity by quercetin, due to the electrospinning process itself and the physical interactions with the polymer. The dissolution assays confirmed that the nanofibers and quercetin completely dissolved in the medium. This dissolution process reached equilibrium within 3 min. Although the material would not be effective as a controlled drug delivery device, it would be effective as a dissolvable film. The quick dissolution of both the drug and the matrix is attractive for the administration of quercetin because it would increase the bioavailability of the drug in the body, overcoming the limited dissolution of crystalline quercetin.

Biopredictive capability assessment of two dissolution/permeation assays, µFLUX™ and PermeaLoop™, using supersaturating formulations of Posaconazole

The majority of new drug entities exhibits poor water solubility and therefore enabling formulations are often needed to ensure sufficient in vivo bioavailability upon oral administration. Several in vitro tools have been proposed for biopredictive screening of such drug formulations to facilitate formulation development. Among these, combined dissolution/permeation (D/P) assays have gained increasing interest in recent years, since they are presumed to better predict the absorption behavior as compared to single-compartment dissolution assays. Moreover, especially for supersaturating formulations, it has been demonstrated that the presence of an absorption sink better mimics the intraluminal supersaturation performance.The present study aimed to investigate the biopredictive abilities of two in vitro D/P setups to predict intestinal supersaturation and systemic absorption of supersaturable systems. Experiments were performed with a µFLUX™ and PermeaLoop™ apparatus, respectively, which differ primarily in their volume-to-area ratios between donor compartment and membrane as well as in the type of biomimetic barrier. A two-stage dissolution protocol was adopted to mimic the transit from acidic stomach to more neutral intestinal fluids using biomimetic media. Three formulations of the weakly basic compound Posaconazole (PCZ), namely an acidified and a neutral suspension and an amorphous solid dispersion (ASD) tablet, were tested.Under the present conditions, and for the specific set of formulations studied here, PermeaLoop™ showed a better biopredictive ability for intestinal supersaturation and systemic absorption for the three formulations than the µFLUX™ D/P setup. Interestingly, minor modifications of the two-stage D/P protocol in terms of medium transfer rates from simulated gastric fluid (SGF) to fasted state simulated intestinal fluid (FaSSIF) had a substantial impact particularly on the permeation of the crystalline PCZ suspension (“acidified suspension”). The ASD tablet was less sensitive to gradual medium changes than the crystalline PCZ suspensions. The current study confirms the usefulness of D/P assays for formulation ranking of weakly basic compounds and supersaturating formulations.

Optimum Extraction Condition of Anacardium occidentale on Antiurolithiatic Activities (in-vitro)

Urolithiasis or kidney stone has become a worldwide problem including Malaysia. Its management is depending on surgical procedures that are quite costly and can cause reoccurrence. Anacardium occidentale (cashew) has been used traditionally to treat urolithiasis but no scientific data has been recorded that proven its efficiency particularly on its extraction parameters. Therefore, this study aims to identify the optimum extraction parameters of A. occidentale leaves extracts on in-vitro antiurolithiatic activities using Response Surface Methodology (RSM). The effect of three extraction parameters (solvent concentration, X1; extraction temperature, X2; extraction time, X3) on antiurolithiatic activities (turbidity or nucleation assay, Y1; titrimetric or calcium oxalate dissolution assay, Y2) were determined by Central Composite Design (CCD). The results showed that each parameter and its interaction significantly affect the antiurolithiatic activities (p &lt; 0.05). The quadratic model was closely fitted for all responses as the R2 values obtained were 0.9786 (turbidity assay) and 0.9956 (titrimetric assay). The optimum extraction condition of A. occidentale leaves extract suggested by the predicted model was at 0.4% ethanol concentration, temperature 31.5 ℃ and for 30 min of extraction time, exhibited antiurolithiatic activities of 85.57 ± 0.43% (turbidity) and 96.48 ± 0.70% (titrimetric). The phytochemical screening was done on the presence of phenols, tannins, flavonoids, alkaloids, saponins as well as terpernoids and all phytochemicals were identified in the optimized A. occidentale leaves extract. This study has given basic scientific evidence that optimum extraction conditions are necessary to obtain optimum antiurolithiatic activity.

Design and development of bilayer tablets containing Zaltoprofen (sustained release) and hibiscus Rosa sinensis leaf powdered Nano crystals (immediate release) for arthritis

The primary objective of this study was to formulate bilayer tablets of Zaltoprofen (sustained release) and Hibiscus Rosa Sinensis Leaf Powder (immediate release) in which the dose of Zaltoprofen was 500 mg and the dose of Hibiscus Rosa Sinensis Leaf Powder was 1 mg and 2 mg. The tablets were prepared by wet granulation. In this study, Hibiscus Rosa Sinensis Leaf Powder layer was formulated in the form of immediate release as an initial dose and Zaltoprofen layer was in the form of sustained release to act as maintenance dose. The sustained release layer of Zaltoprofen was prepared by using HPMC K100 M polymer. The prepared tablets were evaluated for various physicochemical parameters such as drug-excipient interaction by FTIR, flow properties, hardness, weight variation, thickness, friability, disintegration time for Hibiscus Rosa Sinensis Leaf Powder layer, in vitro dissolution studies, assay and uniformity of content. The formulated tablets were found to be similar in drug release profile to that of market sample. These tablets were also subjected for real time and accelerated stability studies as per ICH guidelines. These tablets were found to be stable even after 6 months of stability study as all the parameters were within limit as per the specifications.

IN VITRO DRUG RELEASE STUDY OF CHLORAMPHENICOL IN SITU GEL WITH BASES MIXTURE OF POLOXAMER 407 AND HPMC BY OPTIMIZATION WITH FACTORIAL DESIGN

Objective: The objective of this study was to find the best base mixture composition (poloxamer 407 and HPMC) of chloramphenicol in situ gel formula based on in vitro property (Cumulative amount of drug release).&#x0D; Methods: The in vitro diffusion of chloramphenicol in situ gel study was carried out using franz diffusion cells to know the effect of the Critical Process Parameters (CPPs) as independent variables (poloxamer 407 and hydroxypropyl methylcellulose (HPMC)) on the Critical Quality Attribute (CQA) as dependent variable (cumulative amount of drug release) with 22 factorial design.&#x0D; Results: 22 factorial design of chloramphenicol in situ gel yielded 4 variations of poloxamer 407 and HPMC bases component in %w/v as follows, F1 (5:0.45), F2 (10:0.45) F3 (5:1) and F4 (10:1). The amount of drug release results from in vitro dissolution assay were 30.60% (F1), 45.64% (F2), 58.30% (F3), and 22.50%) (F4).&#x0D; Conclusion: Formula 3 (F3) was considered as the best formula component in terms of in vitro assay of chloramphenicol in situ gel with a desirability value of 0.58.

Analytical Method Development of Content and Dissolution Assay of Ursodeoxycholic Acid Capsule

Ursodeoxycholic acid is an active compound to treat cholesterol gallstones which is included in Biopharmaceutical Classification System class II. Ursodeoxycholic acid capsule formulations have been developed by the pharmaceutical industries. Due to requirement, active ingredient testing and dissolution tests need to be routinely carried out to control quality of the drug. Therefore, aim of this study was to develop a simultaneously analytical method for assay and dissolution test. Optimum condition of analysis were using HPLC-RID, C 18 column (5 µm; 3.9 x 300 mm), flow rate 1 mL/min, 50 µL volume injection, acetonitrile:buffer phosphate pH 3.0 (55:45 v/v) as mobile phase, column, detector, and sample temperature were 40 o C. This method provides good linearity in a range of 50-130 % concentration for assay and dissolution test with correlation coefficient values of 1 and 0.9995, respectively. LOD and LOQ for assay were in value of 4.892 µg/mL and 14.824 µg/mL whereas for dissolution tests in a value of 6,501 µg/mL and 19,701 µg/mL. The average percent recovery for assay and dissolution test were in a range of 100.018±0.888% and 98.936±2.124 %. Repeatability and intermediate precision of assay were obtained by determining RSD values of 0.466% and 0.279-0.483 %, while the dissolution test were 1.137% and 0.032-0.289 %. The validation show this method are linear, selective, accurate, and precise. Keywords: Assay, dissolution test, Ursodeoxycholic acid, validation