Isolation, characterization and anti-inflammatory activity of compounds from the Vernonia amygdalina.

The need to explore the abundance of natural products cannot be overemphasized particularly in the management of various disease conditions. In traditional medical practice, Vernonia amygdalina has been widely adopted in the management of various inflammatory disorders. The objective of this investigation was to isolate the bioactive principles from the stem-bark and root of V. amygdalina and assess the anti-inflammatory (in vitro) activity of both the crude extracts and the isolated compounds. Following extraction with the methanol, the extract was subjected to gravity column chromatography and the resultant fractions was further purified to obtained pure compounds. The structural elucidation of the compounds were based on data obtained from 1H to 13C nuclear magnetic resonance (NMR) spectroscopies as well as fourier transform infrared (FT-IR). Using diclofenac as a control drug, the albumin denaturation assay was used to determine the in vitro anti-inflammatory activity of the extracts and isolates. Three distinct compounds characterized are vernoamyoside D, luteolin-7-α-o-glucuronide, and vernotolaside, a new glycoside. When compared to diclofenac, which has an IC50 of 167.8 µg/mL, luteolin-7-α-o-glucuronide, vernoamyoside D, and vernotolaside all showed significant inhibitions with respective IC50 values 549.8, 379.5, and 201.7 µg/mL. Vernotolaside is reported for the first time from the root. The assertion that the plant is used in traditional medicine for the management of inflammatory disorder is somewhat validated by the confirmation of the existence of the compounds with the biochemical actions. Further validation of the isolated compounds would be required in animal studies.

Enhancing the Topical Antibacterial Activity of Fusidic Acid via Embedding into Cinnamon Oil Nano-Lipid Carrier.

Presently, antimicrobial resistance is of great risk to remarkable improvements in health conditions and infection management. Resistance to various antibiotics has been considered a great obstacle in their usage, necessitating alternative strategies for enhancing the antibacterial effect. Combination therapy has been recognized as a considerable strategy that could improve the therapeutic influence of antibacterial agents. Therefore, the aim of this study was to combine the antibacterial action of compounds of natural origin like fusidic acid (FA) and cinnamon essential oil (CEO) for synergistic effects. A distinctive nanoemulsion (NE) was developed using cinnamon oil loaded with FA. Applying the Box-Behnken design (BBD) approach, one optimized formula was selected and integrated into a gel base to provide an FA-NE-hydrogel for optimal topical application. The FA-NE-hydrogel was examined physically, studied for in vitro release, and investigated for stability upon storage at different conditions, at room (25 °C) and refrigerator (4 °C) temperatures, for up to 3 months. Ultimately, the NE-hydrogel preparation was inspected for its antibacterial behavior using multidrug-resistant bacteria and checked by scanning electron microscopy. The FA-NE-hydrogel formulation demonstrated a pH (6.32), viscosity (12,680 cP), and spreadability (56.7 mm) that are acceptable for topical application. The in vitro release could be extended for 6 h, providing 52.0%. The formulation was stable under both test conditions for up to 3 months of storage. Finally, the FA-NE-hydrogel was found to inhibit the bacterial growth of not only Gram-positive but also Gram-negative bacteria. The inhibition was further elucidated by a scanning electron micrograph, indicating the efficiency of CEO in enhancing the antibacterial influence of FA when combined in an NE system.

The Formulation and Evaluation of Melaleuca alternifolia Cheel and Cymbopogon flexuosus Linn Essential Oils Emulgel for the Treatment of Vulvovaginal Candidiasis.

The global concern regarding the occurrence of antifungal resistance to synthetic conventional azoles used for treating vulvovaginal candidiasis, along with the associated side effects, is significant. Consequently, the pursuit for substitutes such as natural therapies has ensued. Essential oils, derived from plants, have been extensively researched and found to possess antibacterial and antifungal properties. This study aimed to assess the antifungal efficacy of two essential oils, both alone and in combination, against Candida albicans. Essential oils were formulated into an emulgel separately and as combinations. The essential oils of Melaleuca alternifolia and Cymbopogon flexuosus were used in this study. The resulting emulgel formulations were characterized for their antifungal activity against Candida albicans. Physiochemical properties such as pH, viscosity, and appearance were also determined. The prepared emulgels were thereafter observed for stability over a period of 1 month. The MIC of Melaleuca alternifolia was seen to be 50 µL/mL while Cymbopogon flexuous was seen to be more potent at 25 µL/mL against C. albicans exhibiting strong synergistic effect at 0.4. The emulgel formed was white in color, smooth on skin, and had the odor of the essential oils, which is sweet to the nose. The pH of the formulations with the essential oils were acidic in the range of 3.70-3.83, making them suitable for vagina application. The emulgels had viscosities ranging from 4417.6 to 8968.7 mPas, owing to the thickness of the essential oils contained. The emulgel formulation with the combination of essential oils was more potent that the two with individual essential oils; furthermore, the one with Cymbopogon flexuous was more potent than the one with Melaleuca alternifolia. Based on the properties of the formulated emulgels and their activity against the test organism, the preparations have significant potential in the management of vulvovaginal candidiasis.

Formulation of Entandrophragma utile into an Herbal Emulgel for the Management of Inflammation.

Introduction: Globally, the incidence of inflammation and inflammatory disorders has continued to rise at an alarming rate. Entandrophragma utile is a species of flowering plant widely distributed in Africa and has been used for the management of sickle cell disease, rheumatism, ocular inflammation, duodenal and stomach ulcers. This research aims to formulate and evaluate an anti-inflammatory herbal emulgel using an extract from Entandrophragma utile stem bark (EUB). Method: Using a carrageenan-induced paw oedema model, the anti-inflammatory efficacy of EUB the extract was assessed. The formulated Entandrophragma utile emulgels (EUE) were characterized, and their anti-inflammatory activity was demonstrated, by utilizing diclofenac emulgel-treated rats with complete Freund's adjuvant (CFA)-induced arthritis model as the positive control group. Results: The emulgels formulated had characterization results within acceptable ranges; pH (4.25-5.80), viscosity (418.9-112.8 mPas), spreadability (25.00-31.82 gcm/s), extrudability (30.86-51.02 g/cm2), and a swelling index of (30-60%). The emulgel produced a concentration-dependent inflammatory inhibition with a peak effect (117.97%) at the end of the 4th week which was comparable to that of commercial diclofenac (127.19%). The phytochemical analysis led to the identification of saponins, flavonoids, phenols, and tannins as active secondary metabolites. Conclusions: The stem bark extract of E. utile possessed noteworthy (p < 0.05) reduction in inflammation in comparison to diclofenac and its emulgel formulation showed enormous potential for treating inflammation and pain.

Network Pharmacology and Molecular Modeling to Elucidate the Potential Mechanism of Neem Oil against Acne vulgaris.

Acne vulgaris is a common skin disorder with a complicated etiology. Papules, lesions, comedones, blackheads, and other skin lesions are common physical manifestations of Acne vulgaris, but the individual who has it also regularly has psychological repercussions. Natural oils are being utilized more and more to treat skin conditions since they have fewer negative effects and are expected to provide benefits. Using network pharmacology, this study aims to ascertain if neem oil has any anti-acne benefits and, if so, to speculate on probable mechanisms of action for such effects. The neem leaves (Azadirachta indica) were collected, verified, authenticated, and assigned a voucher number. After steam distillation was used to extract the neem oil, the phytochemical components of the oil were examined using gas chromatography-mass spectrometry (GC-MS). The components of the oil were computationally examined for drug-likeness using Lipinski's criteria. The Pharm Mapper service was used to anticipate the targets. Prior to pathway and protein-protein interaction investigations, molecular docking was performed to predict binding affinity. Neem oil was discovered to be a potential target for STAT1, CSK, CRABP2, and SYK genes in the treatment of Acne vulgaris. In conclusion, it was discovered that the neem oil components with PubChem IDs: ID_610088 (2-(1-adamantyl)-N-methylacetamide), ID_600826 (N-benzyl-2-(2-methyl-5-phenyl-3H-1,3,4-thiadiazol-2-yl)acetamide), and ID_16451547 (N-(3-methoxyphenyl)-2-(1-phenyltetrazol-5-yl)sulfanylpropanamide) have strong affinities for these drug targets and may thus be used as therapeutic agents in the treatment of acne.

Polypharmacology of some medicinal plant metabolites against SARS-CoV-2 and host targets: Molecular dynamics evaluation of NSP9 RNA binding protein.

Medicinal plants as rich sources of bioactive compounds are now being explored for drug development against COVID-19. 19 medicinal plants known to exhibit antiviral and anti-inflammatory effects were manually curated, procuring a library of 521 metabolites; this was virtually screened against NSP9, including some other viral and host targets and were evaluated for polypharmacological indications. Leads were identified via rigorous scoring thresholds and ADMET filtering. MM-GBSA calculation was deployed to select NSP9-Lead complexes and the complexes were evaluated for their stability and protein-ligand communication via MD simulation. We identified 5 phytochemical leads for NSP9, 23 for Furin, 18 for ORF3a, and 19 for IL-6. Ochnaflavone and Licoflavone B, obtained from Lonicera japonica (Japanese Honeysuckle) and Glycyrrhiza glabra (Licorice), respectively, were identified to have the highest potential polypharmacological properties for the aforementioned targets and may act on multiple pathways simultaneously to inhibit viral entry, replication, and disease progression. Additionally, MD simulation supports the robust stability of Ochnaflavone and Licoflavone B against NSP9 at the active sites via hydrophobic interactions, H-bonding, and H-bonding facilitated by water. This study promotes the initiation of further experimental analysis of natural product-based anti-COVID-19 therapeutics.

Evaluation of the antidiarrheal activity of the leaf extract of Parquetina nigrescens and formulation into oral suspensions.

PURPOSE: Parquetina nigrescens (Pn) extract was evaluated for safety and antidiarrheal activity, formulated into stable suspensions, and characterized. METHODS: Acute toxicity of the extract based on Organization for Economic Cooperation and Development-423 guidelines was performed. The antidiarrheal effects of the extract on castor oil-induced diarrhea in four groups of Wistar rats were determined. The first and second groups received 5 and 200 mg/kg body weight (bw) of the extract, while the third and fourth groups received normal saline (5 mg/kg bw) and loperamide (5 mg/kg bw) as negative and positive controls, respectively. Pn extract was used at 1.25% w/v to formulate structured vehicle (carboxylmethylcellulose, polyvinylpyrrolidone and tragacanth) suspensions. The suspensions were tested for pharmacological activity and characterized. RESULTS: Acute toxicity gave a lethal dose 50 (LD50) that is greater than 300 and less than 2,000 mg/kg bw. A reduction in intestinal transit by 0.14 and 0.15% at 5 and 200 mg/kg of the extract was achieved as compared to an inhibition of 0.12% by 5 mg/kg loperamide. There was a dose-dependent decrease in the frequency of watery stool passed in castor oil-induced rats by 35.29% and 64.70% at 5 and 200 mg/kg, respectively. All the suspensions inhibited diarrhea, exhibiting a dose-dependent pattern and remained stable after 4 weeks. Their pH values ranged from 4.60±2.73 to 4.73±1.91, while viscosity ranged from 3.50±1.23 to 6.75±1.24 Pas at 60 rpm. CONCLUSION: The results suggest that Pn possesses significant antidiarrheal activity. Suspensions of Pn were successfully formulated in structured vehicles and were effective in the control of diarrhea in Wistar rats.

The use of herbal medicines amongst outpatients at the University of Ilorin Teaching Hospital (UITH), Ilorin, Kwara State - Nigeria.

BACKGROUND: In Africa, particularly Nigeria, there is an increasing interest in natural product remedies with a basic approach towards nature. This research studies the prevalence of use, pattern of use and awareness of outpatients at the University of Ilorin Teaching Hospital, Ilorin, Nigeria on the use of herbal medicines. METHODOLOGY: Based on an informed consent, semi-structured questionnaires were used to collect data from a total of 112 outpatients attending different outpatient clinics of the hospital about the use of herbs. This sample size was derived from the Kish formula. Data obtained were analyzed by IBM SPSS Statistics software V23 and inferences made accordingly. RESULTS: All (100.00%) of the outpatients were familiar with herbal medicines, 67.86% had used herbal medicines in the past and 25.00% were currently taking herbal medicines as at the time of study. It was also found that 54.35% of the respondents use herbal medicines in no specific dose, 47.83% use the herbs with various additives, and 39.13% take their herbs concurrently with orthodox medicines. A total of 13.73% of the respondents prefer to use herbs when sick and another 35.29% prefer a combination of herbs and orthodox medicines. CONCLUSIONS: Most of the patient-respondents prefer to include herbal medicines in their therapies. It is concerning that over one-third of the respondents concomitantly use herbal and orthodox medicines, some others use the herbs inappropriately. More efforts should be geared towards ensuring general improved use of herbal medicines.

Development of aqueous ternary nanomatrix films: A novel 'green' strategy for the delivery of poorly soluble drugs.

Aqueous polymeric films have potentially great values in drug development, particularly in controlled drug release and taste masking strategies. However the progressive polymer-particle coalescence that occurs randomly during film formation, curing and storage may render the film less permeable leading to erratic and unpredictable drug release profile. The focus of this study was to investigate the impacts of the in situ formation of polymer-drug nanoconjugate, at the interfacial nano-domains of two oppositely charged polymers, on the mechanism of film formation and to prepare aqueous ternary polymer-drug-polymer nanomatrix films as a novel green strategy for the delivery of ibuprofen, a model poorly soluble drug. Composite and Layer-by-Layer films were prepared by aqueous casting technique using the concept of combined polymer-drug self-assembly and polyelectrolyte complexation. The plain and drug-loaded nanomatrix films were characterized using SEM, AFM, FTIR, DSC and TGA. Ibuprofen formed spherical core-shell microstructures (4.55-9.73µm) in gellan film. However in the presence of cationic dextran (Ddex), nanoconjugates (61.49±5.97-447.52±37.51nm) were formed within the core of the film matrix. The composite films exhibited reduced tensile strength and lower elastic modulus with optimal conjugation efficiency of 98.14±1.19%, which correlates with higher dissolution efficiency (99.76%) compared to 47.37% in layer-by-layer (LbL) films, dictated by Ddex concentration. Generally, the mechanism of drug release was by Fickian diffusion, however anomalous transport or polymer relaxation was also observed at higher concentration of Ddex. This study demonstrated the potential application of aqueous drug-loaded nanomatrix films as controlled drug delivery strategy for ibuprofen, a model poorly soluble drug.

Thermodynamic Changes Induced by Intermolecular Interaction Between Ibuprofen and Chitosan: Effect on Crystal Habit, Solubility and In Vitro Release Kinetics of Ibuprofen.

PURPOSE: The direct impact of intermolecular attraction between ibuprofen and chitosan on crystal behaviour, saturated solubility and dissolution efficiency of ibuprofen was investigated in order to expand the drug delivery strategy for ibuprofen. METHODS: Amorphous nanoparticle complex (nanoplex) was prepared by controlled drug-polymer nanoassembly. Intermolecular attraction was confirmed with surface tension, conductivity measurements and FTIR spectroscopy. The nanoplex was characterized using DSC, TGA and SEM. The in vitro release kinetics and mechanism of drug release were evaluated using mathematical models. RESULTS: The cmc of ibuprofen decreased significantly in the nanoplex (1.85 mM) compared with pure ibuprofen (177.62 mM) suggesting a remarkable affinity between the chitosan and ibuprofen. The disappearance of ibuprofen melting peak in the nanoplex and the broadened DSC endothermic peaks of the nanoplex indicate formation of eutectic amorphous product which corresponded to higher saturated solubility and dissolution velocity. Ibuprofen (aspect ratio 5.16 ± 1.15) was converted into spherical nanoparticle complex with particle size of 14.96 ± 1.162-143.17 ± 17.5247 nm (36-345 folds reduction) dictated by chitosan concentration. Pure ibuprofen exhibited burst release while the nanoplexes showed both fast and extended release profiles. DE increased to a maximum (81.76 ± 2.1031%) with chitosan concentrations at 3.28 × 10-3 g/dm3, beyond which retardation occurred steadily. Major mechanism of drug release from the nanoplex was by diffusion however anomalous transport and super case II transport did occur. CONCLUSION: Ibuprofen-chitosan nanoplex exhibited combined fast and extended release profile dictated by chitosan concentration. This study demonstrated the potential application of drug-polymer nanoconjugate design in multifunctional regulated drug delivery.

Formulation studies on ibuprofen sodium-cationic dextran conjugate: effect on tableting and dissolution characteristics of ibuprofen.

The effect of electrostatic interaction between ibuprofen sodium (IbS) and cationic diethylaminoethyl dextran (Ddex), on the tableting properties and ibuprofen release from the conjugate tablet was investigated. Ibuprofen exhibits poor flow, compaction (tableting) and dissolution behavior due to its hydrophobic structure, high cohesive, adhesive and viscoelastic properties therefore it was granulated with cationic Ddex to improve its compression and dissolution characteristics. Electrostatic interaction and hydrogen bonding between IbS and Ddex was confirmed with FT-IR and DSC results showed a stepwise endothermic solid-solid structural transformation from racemic to anhydrous forms between 120 and 175 °C which melted into liquid form at 208.15 °C. The broad and diffused DSC peaks of the conjugate granules as well as the disappearance of ibuprofen melting peak provided evidence for their highly amorphous state. It was evident that Ddex improved the flowability and densification of the granules and increased the mechanical and tensile strengths of the resulting tablets as the tensile strength increased from 0.67 ± 0.0172 to 1.90 ± 0.0038 MPa with increasing Ddex concentration. Both tapping and compression processes showed that the most prominent mechanism of densification were particle slippage, rearrangement and plastic deformation while fragmentation was minimized. Ddex retarded the extent of dissolution in general, indicating potentials for controlled release formulations. Multiple release mechanisms including diffusion; anomalous transport and super case II transport were noted. It was concluded that interaction between ibuprofen sodium and Ddex produced a novel formulation with improved flowability, tableting and dissolution characteristics with potential controlled drug release characteristics dictated by Ddex concentration.

Formulation and Physical Characterization of Ibuprofen-DEAE-Dextran Nanoconjugates via Surfactant Solubilization

Background: The optimization of polymer-drug conjugate design is important in effective and efficient delivery of poorly soluble drugs. Objectives: This work focuses on the formulation of novel amorphous ibuprofen-polymer nanoconjugates based on the polymer-drug complexation in order to improve its physical characteristics in the absence of toxic organic solvents. Methods: Amorphous Ibuprofen - DEAE-Dextran nanoconjugates were prepared using surfactant solubilization method. Physical characterization of the nanoconjugates was carried out via conductivity; surface tension; viscosity; transmittance/turbidity; particle size measurement; zeta potential; conjugation efficiency and Scanning Electron Microscopy (SEM) techniques. Results: A remarkably high loading capacity was achieved ranging from 89.05 to 96.34%. The conductivity measurements showed that the critical association concentration (cac) was exhibited at 2.34 mg/mL and critical micellar concentration (cmc) at 8.0 mg/mL. The presence of DEAE-Dextran decreased the cac of ibuprofen significantly (p 0.05; n

Ex vivo skin permeation and retention studies on chitosan-ibuprofen-gellan ternary nanogel prepared by in situ ionic gelation technique--a tool for controlled transdermal delivery of ibuprofen.

The chemical potentials of drug-polymer electrostatic interaction have been utilized to develop a novel ternary chitosan-ibuprofen-gellan nanogel as controlled transdermal delivery tool for ibuprofen. The ternary nanogels were prepared by a combination of electrostatic nanoassembly and ionic gelation techniques. The electrostatic and hydrophobic interactions as well as hydrogen bonding between ibuprofen and chitosan were confirmed with FTIR, while DSC, TGA and SEM confirmed the physical state, thermal and morphological characteristics, respectively. The ex vivo delivery of ibuprofen onto and across the skin was evaluated based on system specific drug release parameters such as steady state permeation rate, permeability coefficient, permeability enhancement ratio, skin/gel partition coefficient, diffusion coefficient, lag time and release rate constant and mechanisms of release were determined using mathematical models. Interaction between ibuprofen and chitosan produced new spherical eutectic nanoconjugates with remarkable decrease in particle size of ibuprofen from 4580 (length-to-breadth aspect ratio) to a minimum of 14.15 nm (324-times), and thermally stable amorphous characteristics. The nanogels exhibited significant elastic and pseudoplastic characteristics dictated by the concentration of chitosan with maximum swelling capacity of 775% w/w at 6.55 mM chitosan compared with 281.16 and 506.50% for plain gellan and control ibuprofen hydrogel, respectively. Chitosan enhanced the skin penetration, permeability and the rate of transdermal release of ibuprofen by a factor of 4, dictated by the extent of ibuprofen-chitosan ionic interaction and its concentration. The major mechanism of ibuprofen release through the pig skin was drug diffusion however drug partition and matrix erosion also occurred. It was evident that ternary nanogels are novel formulations with potential application in controlled transdermal delivery of ibuprofen.

Controlled Electrostatic Self-Assembly of Ibuprofen-Cationic Dextran Nanoconjugates Prepared by low Energy Green Process - a Novel Delivery Tool for Poorly Soluble Drugs.

PURPOSE: The direct effect of electrostatic interaction between ibuprofen and cationic dextran on the system-specific physicochemical parameters and intrinsic dissolution characteristics of ibuprofen was evaluated in order to develop drug-polymer nanoconjugate as a delivery strategy for poorly soluble drugs. METHODS: Amorphous ibuprofen-DEAE dextran (Ddex) nanoconjugate was prepared using a low energy, controlled amphiphile-polyelectrolyte electrostatic self-assembly technique optimized by ibuprofen critical solubility and Ddex charge screening. Physicochemical characteristics of the nanoconjugates were evaluated using FTIR, DSC, TGA, NMR and SEM relative to pure ibuprofen. The in vitro release profiles and mechanism of ibuprofen release were determined using mathematical models including zero and first order kinetics; Higuchi; Hixson-Crowell and Korsmeyer-Peppas. RESULTS: Electrostatic interaction between ibuprofen and Ddex was confirmed with FT-IR, (1)H NMR and (13)C NMR spectroscopy. The broad and diffused DSC peaks of the nanoconjugate as well as the disappearance of ibuprofen melting peak provided evidence for their highly amorphous state. Low concentrations of Ddex up to 1.0 × 10(-6) g/dm(3) enhanced dissolution of ibuprofen to a maximum of 81.32% beyond which retardation occurred steadily. Multiple release mechanisms including diffusion; discrete drug dissolution; anomalous transport and super case II transport were noted. CONCLUSIONS: Controlled assembly of ibuprofen and Ddex produced a novel formulation with potential extended drug release dictated by Ddex concentration.

Quantification of in situ granulation-induced changes in pre-compression, solubility, dose distribution and intrinsic in vitro release characteristics of ibuprofen-cationic dextran conjugate crystanules.

The direct effect of intermolecular association between ibuprofen and diethylaminoethyl dextran (Ddex) and the novel 'melt-in situ granulation-crystallization' technique on the solubility, dose distribution, in vitro dissolution kinetics and pre-compression characteristics of the ibuprofen-Ddex conjugate crystanules have been investigated using various mathematical equations and statistical moments. The research intention was to elucidate the mechanisms of ibuprofen solubilization, densification and release from the conjugate crystanules as well as its dose distribution in order to provide fundamental knowledge on important physicochemical, thermodynamic and system-specific parameters which are key indices for the optimization of drug-polymer conjugate design for the delivery of poorly soluble drugs. The process of melt-in situ-granulation-crystallization reduced the solubility slightly compared with pure ibuprofen, however, the ibuprofen-Ddex conjugate crystanules exhibited increased ibuprofen solubility to a maximum of 2.47×10(-1) mM (at 1.25×10(-4) mM Ddex) and 8.72×10(-1) mM (at 6.25×10(-4) mM Ddex) at 25 and 37 °C, respectively. Beyond these concentrations of Ddex ibuprofen solubility decreased steadily due to stronger bond strength of the conjugate crystanules. The enthalpy-entropy compensation plot suggests a dominant entropy-driven mechanism of solubilization. In the same vein, the addition of Ddex increased the rate and extent of in vitro ibuprofen release from the conjugate crystanule to 100% within 168 h at Ddex concentration of 1.56×10(-4) mM, followed by a decrease with Ddex concentration. The conjugate crystanules exhibited controlled and extended-complete release profile which appeared to be dictated by the concentration of the Ddex and its strong affinity for ibuprofen. A comparison of the real experimental with the predicted data using artificial neural network shows excellent correlation between solubility and dissolution profiles (average error=0.2348%). Heckel, Kawakita, Cooper-Eaton and Kuno equations were employed to determine the mechanism of densification during tapping process. Ddex in the crystanules consistently improved particle rearrangement in the order of 2.5-7 folds compared with pure ibuprofen and stabilized ibuprofen against fragmentation during tapping process. Primary and secondary particle rearrangements were the prominent mechanisms of densification while deformation and fragmentation did not occur. Lower concentrations of Ddex below its critical granular concentration (<6.25×10(-4) mM) hindered plastic deformation and fragmentation, however, the summation of primary and secondary rearrangement parameters was greater than unity suggesting that the overall rearrangement of the conjugate crystanules cannot be explained exclusively by these two steps. This study has demonstrated the formulation of a novel ibuprofen-polymer conjugate which exhibited improved dose distribution and pre-compression characteristics as well as controlled and extended-complete release profiles - a potential drug delivery strategy for poorly soluble drugs.

Impact of in situ granulation and temperature quenching on crystal habit and micromeritic properties of ibuprofen-cationic dextran conjugate crystanules.

Ibuprofen was recrystallized in the presence of aqueous solution of cationic dextran derivative, Diethylaminoethyl Dextran (Ddex) using the melt-in situ granulation-crystallization technique in order to produce a stable amorphous ibuprofen-Ddex conjugates with improved morphological, micromeritic and thermo-analytical characteristics without the use of organic solvent. Ddex was used in this study because of its ability to form conjugates with various drug molecules and enhance their physicochemical characteristics and therapeutic activities. Cationic dextrans are also biocompatible and biodegradable. Mechanism of conjugation as well as the impact of conjugation on the ibuprofen crystal habit was investigated. Gaussian type normal particle size distribution was obtained and the size of the crystals in the crystanule conjugates decreased steadily, with increasing concentration of Ddex, to a minimum of 480 nm (440-folds reduction, p<0.05, n=20) at Ddex molar concentration of 0.01 mM. FT-IR spectra showed electrostatic interaction and hydrogen bonding between ibuprofen and Ddex which was confirmed with the (1)H NMR and (13)C NMR spectra. DSC curves exhibited single peaks from the binary ibuprofen-Ddex conjugate crystanules suggesting compatibility and formation of an eutectic product. The conjugate crystanules showed broad and diffuse endothermic peaks with a glass transition temperature (T(g)) of 58.3 and 59.14°C at Ddex molar concentrations of 1.56 × 10(-4) and 3.125 × 10(-4)mM respectively confirming the existence of ibuprofen-Ddex crystanule conjugates in amorphous state. Higher concentrations of Ddex decreased T(g) steadily. TGA curves showed first order degradation at low molar concentrations of Ddex up to 3.125 × 10(-4)mM which coincides with the critical granular concentration of the crystanules while higher concentrations exhibited second order degradation profile. This study provides the basis for the development of stable amorphous drug-polymer conjugates with potential practical application in controlled and extended drug release formulations.