Processing of nimesulide-PEG 400-PG-PVP solid dispersions: preparation,characterization, and in vitro dissolution

The objective of this investigation was to study the influence of dissolution enhancers such as polyethylene glycol 400, propylene glycol, polyvinylpyrrolidone K30, sodium lauryl sulfate, and Tween 80 on in vitro dissolution of a model active pharmaceutical material--nimesulide. Preliminary studies were conducted using a physical blend of nimesulide, and the adjuvants and solid dispersions were prepared using solvent evaporation and cogrinding methods. Aqueous solution of adjuvants was first triturated with nimesulide, followed by mixing with lactose and microcrystalline cellulose, and finally water was evaporated under vacuum in a cogrinding method. A 33 factorial design was adopted in a cogrinding method using the concentration of polyethylene glycol 400, propylene glycol, and polyvinylpyrrolidone K30 as independent variables. Tween 80 and sodium lauryl sulfate were added in all the batches. Full and reduced models were evolved for different dependent variables. The reduced models were validated using two checkpoints. Angle of repose < 35 degrees, percentage of drug released in 30 min (Q30) > 40%, 45 min (Q45) > 50%, and 120 min (Q12) > 60% were used as constraints for the selection of an optimized batch. Contour plots are presented for the selected dependent variables. Polyvinylpyrrolidone was found to be more effective in increasing the drug dissolution, compared with polyethylene glycol 400 and propylene glycol. The granule flow was adversely affected when high levels of liquid adjuvants were used in formulations. Wettability study was conducted to measure wetting time for pure drug and the optimized batch. Improved drug dissolution was attributed to improved wetting and the solubilizing effect of adjuvants from the pseudosolid dispersions of nimesulide. Significant improvement in drug dissolution was observed (Q120 = 70%), compared with pure drug powder (Q120 = 15%). In conclusion, dissolution of nimesulide can be modulated using an appropriate blend of pharmaceutical adjuvants.     

Influence of alkalizers on dissolution properties of telmisartan in solid dispersions prepared by cogrinding

The amorphous solid dispersions of telmisartan salts were prepared by cogrinding, in presence of alkalizers and polyvinylpyrrolidone (PVP_k30). Five alkalizers in this study were MgO, Na₂CO₃, K₂CO₃, NaHCO₃ and meglumine. In soft mode using a roll mill, the drug could not form salt with MgO or NaHCO₃, whereas partial drug had been transformed into salt with carbonates or meglumine. Under cogrinding, the organic base meglumine was easier to react with telmisartan than other two carbonates. For getting good dissolution performance, the drug had to be transformed into salt completely. A high intensity oscillating mill was applied for producing telmisartan meglumine salt. Multi-instrumental characterizations attested the formation of amorphous salt by high mechanical process, involving dissolution test, fourier transform infrared spectroscopy and powder X-ray diffractometry. It was evident that solid dispersions of telmisartan meglumine salt significantly increased the drug dissolution rate in intestinal fluid.     

A novel application of electrospinning technique in sublingual membrane: characterization,permeation and in vivo study

Isosorbide dinitrate–polyvinylpyrrolidone (ISDN–PVP) electrospinning fibers were formulated and explored as potentially sublingual membrane. The addition of polyethylene glycol (PEG) to the formulation improved flexibility and reduced fluffiness of the fiber mat. The scanning electron microscopy (SEM) demonstrated that the fibers tended to be cross-linking, and the crosslinking degree increased with the increase of PEG amount. The differential scanning calorimetry (DSC) indicated that ISDN existed in non-crystalline state in the fibers (except at the highest drug content). The infrared spectroscopy suggested that ISDN had better compatibility with the ingredients owing to the hydrogen bonding (or hydrophobic interactions). The fibers were highly favorable for the fabrication of sublingual membrane due to neutral pH, large folding endurance and rapid drug release (complete dissolution within 120 s). The permeation study of ISDN through both dialysis membrane (DM) and porcine sublingual mucosa (SM) were carried out. A significant relationship of drug permeation rate through DM and SM was built up, which indicated that DM could be used to partly simulate SM and assess formulation. The pharmacokinetic study in rats demonstrated that the electrospinning fiber membrane had a higher C_max and lower T_max compared to the reference preparation, and the relative bioavailability of the fiber membrane was 151.6%.     

Ketoprofen Suppository Dosage Forms: In Vitro Release and in Vivo Absorption Studies in Rabbits

In vitro release of ketoprofen from suppository bases and in vivo absorption in rabbits were studied. Suppositories containing 50 mg of ketoprofen were prepared using theobroma oil, esterified (c₁₀–c₁₈) fatty acids, and polyethylene glycol 1000 bases. The displacement values of the drug were determined and found to be of the order of theobroma oil > esterified (c₁₀–c₁₈) fatty acids and polyethylene glycol 1000 bases. The suppository hardness data revealed that the theobroma oil base produced relatively brittle suppositories. Using the USP dissolution method, the release of ketoprofen was observed to be greatest from polyethylene glycol 1000 suppositories. With the dialysis technique, the maximum release of drug was obtained from theobroma oil suppository containing polysorbate 40 at a 6% level. Selected suppository formulations were evaluated for rectal absorption studies in rabbits. The in vivo data showed that the optimum drug absorption took place from the polyethylene glycol 1000 base and theobroma oil formulation containing 6% polysorbate 40.     

Effects of Cellulose Derivatives and Additives in the Spray-Drying Preparation of Acetaminophen Delivery Systems

Microcrystalline cellulose (MCC), sodium carboxymethylcellulose (NaCMC), hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), hydroxypro pylcellulose (HPC), and ethylcellulose (EC) were used for the production of time-controlled acetaminophen delivery systems using a spray-drying technique. The influence of factors such as polymer concentration, inlet temperature, and drug/polymer ratio were investigated. The product yields were a function of the type and concentration of the polymer, with the highest values being reached from feeds containing 1% MCC and EC. Parameters of 1% polymer concentration and an inlet temperature of 140°C gave rise to optimal processing conditions. Using these parameters, the influence of some adjuncts, such as polyethylene glycol 6000 (PEG 6000), dibutyl sebacate (DBS), polyvinylpyrrolidone (PVP), and carboxylic acids such as citric acid (CA), phthalic acid (PA), succinic acid (SA), tartaric acid (TA), and oxalic acid (OA), on the spray-drying process was evaluated. Of the additives tested, PVP (with MCC), DBS (with EC), and PEG 6000 (with NaCMC) induced yield decreases from 70% to 49%, 66% to 39%, and 37% to 17%, respectively. As for carboxylic acids (with NaCMC), similar or better performances of 43%, 45%, 47%, and 49% were obtained with SA, OA, PA, and TA, respectively. Dissolution studies in pH 1 dilute HCl and pH 6.8 phosphate buffer dissolution media showed that formulations consisting of 1% polymer with a drug/polymer ratio of 1/1 exhibited the slowest drug release, with the spheroids coated with NaCMC and HEC showing the longest T_50% values (with 45 and 53 min at pH 1 and 49 and 55 min at pH 6.8, respectively). Slightly better sustained drug release in pH 6.8 dissolution medium was reached, showing the following trend: HEC > NaCMC > MCC > EC > HPMC. Concerning the additives, the trends in dissolution T_50% of drug revealed TA > SA > CA > OA > PVP > PA > DBS in acidic pH 1 dissolution medium and PVP > OA > TA > SA > PA > CA > DBS in phosphate buffer at pH 6.8.     

Single non-ionic surfactant based self-nanoemulsifying drug delivery systems: formulation,characterization, cytotoxicity and permeability enhancement study

Single non-ionic surfactant based self-nanoemulsifying drug delivery system (SNEDDS) was formulated and characterised for poor water soluble drug, Atorvastatin calcium. Capmul MCM oil showing highest solubility for Atorvastatin calcium was selected as oil phase. Self-nanoemulsifying capacity of Cremophor RH 40, Cremophor EL, Tween 20, Tween 60, Tween 80 and Labrasol were tested for the selected oil. In vitro dissolution studies were performed and were characterized by t85% and dissolution efficiency (DE). Cytotoxicity of the formulations and permeation enhancement of the drug across caco-2 cell monolayer was assessed. Capmul MCM was found to be better nanoemulsified in decreasing order of Cremophor RH 40 > Cremophor EL > Tween 20 > Tween 60 > Tween 80. Values of droplet size (range 11–83 nm), polydispersity index (range 0.07–0.65); zeta potential (range ?3.97 to ?19.0) and cloud point (60–85°C) before and after drug loading proves the uniformity and stability of the formulations. SNEDDS formulated with Tween 20 surfactant showed enhanced dissolution with t85% and DE values at 10 min and 78.70, respectively. None of the formulation showed cytotoxicity at the concentration tested. Tween 20 based SNEDDS enhanced permeation of the drug as compared with pure drug across cell lines. It can be concluded that SNEDDS can be formulated by using single non-ionic surfactant system for enhance dissolution and absorption of poorly soluble drug, Atorvastatin calcium.     

Enhanced dissolution and absorption of trimethoprim from coprecipitates with polyethylene glycols and polyvinylpyrrolidone

Abstract

Coprecipitates of trimethoprim have been prepared by solvent method using polyethylene glycols 4000, 6000 and 9000, and polyvinylpyrrolidone (M.W. 40,000) as water soluble carriers. A marked increase in the dissolution rate of trimethoprim in the coprecipitates was observed compared with that of the drug alone. Coprecipitates with polyethylene glycol 6000 (1:2) showed faster release as well as bioavailability of the drug in human volunteers.     

Kinetics of Alkaline Hydrolysis of Indomethacin in the Presence of Surfactants and Cosolvents

Abstract

The effect of nonionic and ionic surfactants as well as water-miscible cosolvents on the alkaline hydrolysis of indomethacin was investigated. Degradation in the presence and absence of surfactants was found to follow pseudo first-order kinetics. The nonionic surfactant, polysorbate 80, produced a 7-fold increase in the stability of indomethacin. The ionic surfactants, cetrimonium bromide, benzalkonium chloride and sodium lauryl sulphate, also resulted in an increase in the stability of indomethacin but to a lesser extent than polysorbate 80. The order of surfactants in increasing the stability of indomethacin was: polysorbate 80 > sodium lauryl sulphate > benzalkonium chloride > cetrimonium bromide. Polyethylene glycol 400 was found more effective than glycerin and propylene     

Stability of 4-DMAP in Solution

A stability-indicating reversed-phase performance liquid chromatographic method was developed for the detection of 4-(N, N-dimethylamino)phenol (4-DMAP) and its degradation products under accelerated degradation conditions. The degradation kinetics of 4-DMAP in aqueous solution over a pH range of 1.12–6.05 and its stability in solutions based on propylene glycol or polyethylene glycol 400 were investigated. The observed rate constants were shown to follow apparent first-order kinetics in all cases. The pH rate profile shows that maximum stability of 4-DMAP was observed in the pH range 2.0 to 3.0. Acid/base catalysis of 4-DMAP was not affected by systems of various ionic strengths. Incorporation of nonaqueous propylene glycol or polyethylene glycol 400 in the pH 3.05 solution of 4-DMAP showed an increase in the stability at 55°C ± 0.5°C,     

Characterization and Dissolution Properties of Ketoprofen in Binary and Ternary Solid Dispersions with Polyethylene Glycol and Surfactants

The effect of incorporation of an anionic [sodium dodecyl sulfate (SDS) or dioctylsulfosuccinate (DSS)] or nonionic [Tween 60 (TW60)] surfactant on the properties of ketoprofen solid dispersions in polyethylene glycol 15000 (PEG) has been investigated. Physicochemical and morphological properties of the various solid systems were determined by differential scanning calorimetry, hot stage microscopy, X-ray powder diffraction analysis, and scanning electron microscopy. The results from dissolution studies, performed according to the USP 24 basket method, indicated that all ternary dispersed systems were significantly (p < 0.001) more efficacious than the corresponding binary ones, by virtue of the additive wetting and solubilizing effect due to the presence of the surfactant. The relative effectiveness of the incorporated surfactant was in the same order as found in phase-solubility studies (i.e., SDS > DSS > TW60). With regard to the solid dispersion preparation method, coevaporated products always gave better results than the corresponding cofused ones; however, this effect was statistically significant (p < 0.001) only in the initial phase of the dissolution process. The most effective solid dispersion was the 10-80-10 w/w drug-PEG-SDS ternary coevaporate, which allowed dissolution of 50% drug after only 6 min (in comparison with > 120 min for drug alone and 17 min for the binary coevaporate) and dissolution of about 100% drug after 30 min (in comparison with > 120 min for the binary coevaporate).     

Effect of Particle Size on the Dissolution Rate of Monophenylbutazone Solid Dispersion in Presence of Certain Additives

Abstract

Monophenylbutazone is a very sparingly soluble drug. The effect of particle size on the dissolution characteristics of monophenylbutazone in a dissolution medium of 0.1 N hydrochloric acid and 0.1 N hydrochloric acid to which was added 0.005% Tween 80, was carried out. The enhancement of the dissolution rate of the medicament was attained by formulating the drug in both solid dispersion and physical mixture using urea and polyethylene glycol 4000 as carriers. A comparative dissolution behaviour of the medicament in different solid dispersion and physical mixture ratios were investigated at particle, size of < 63 μ. Drug-urea solid dispersion of a ratio 5:95% produced the highest dissolution rate.     

Nimesulide-modified gum karaya solid mixtures: preparation, characterization, and formulation development

Solid mixtures of nimesulide (NS) and modified gum karaya (MGK) were prepared to improve the dissolution rate of NS. The effect of drug-carrier ratio on dissolution rate of NS was investigated by preparing the solid mixtures of different ratios by cogrinding method. Solid mixtures were also prepared by physical mixing, kneading, and solid dispersion techniques to study the influence of method of preparation. Differential Scanning Calorimetry (DSC), X-ray Diffraction (XRD), and equilibrium solubility studies were performed to explain the results of in vitro dissolution rate studies. It was clearly evident from the results that the NS dissolution rate was dependent on the concentration of MGK in the solid mixtures, and optimum weight ratio was found to be 1:4 (NS:MGK). Though the dissolution rate of NS from all solid mixtures prepared by different methods improved significantly, maximum improvement in dissolution rate was observed with solid dispersions. The order of methods basing on their effect on dissolution efficiency is solid dispersion > kneading > cogrinding > physical mixing > pure NS. Tablets of pure drug and solid mixtures (1:4 w/w, NS:MGK) were prepared. Though the best results from the dissolution test were obtained for the tablets containing solid dispersions, tablets containing cogrinding mixture were found to be suitable, from a practical point of view, for commercialization.     

Solubility measurement,Hansen solubility parameters and solution thermodynamics of gemfibrozil in different pharmaceutically used solvents

Gemfibrozil (GEM) is cholesterol-lowering agent which is being proposed as poorly water soluble drug (PWSD). Temperature based solubility values of GEM are not yet available in literature or any pharmacopoeia/monograph. Hence, the present studies were carried out to determine the solubility of PWSD GEM (as mole fraction) in various pharmaceutically used solvents such as water (H₂O), methanol (MeOH), ethanol (EtOH), isopropanol (IPA), 1-butanol (1-BuOH), 2-butanol (2-BuOH), ethylene glycol (EG), propylene glycol (PG), polyethylene glycol-400 (PEG-400), ethyl acetate (EA), dimethyl sulfoxide (DMSO) and Transcutol^® (THP) at the temperatures ranging from T?=?298.2 K–318.2?K under atmospheric pressure P?=?0.1?MPa. Equilibrium/experimental solubilities of GEM were recorded by applying a saturation shake flask methodology and regressed using ‘van’t Hoff and Apelblat models’. Hansen solubility parameters for GEM and various pharmaceutically used solvents were estimated using HSPiP software. The solid states of GEM (both in pure and equilibrated states) were studied by ‘Differential Scanning Calorimetry’ which confirmed no transformation of GEM after equilibrium. Experimental solubilities of GEM in mole fraction were observed maximum in THP (1.81?×?10^?1) followed by DMSO, PEG-400, EA, 1-BuOH, 2-BuOH, IPA, EtOH, PG, MeOH, EG and H₂O (3.24?×?10^?6) at T?=?318.2 K and similar tendencies were also recorded at T?=?298.2 K, T?=?303.2 K, T?=?308.2 K and T?=?313.2 K. ‘Apparent thermodynamic analysis’ on experimental solubilities furnished ‘endothermic and entropy-driven dissolution’ of GEM in each pharmaceutically used solvent.     

Spray-dried solid dispersions containing ferulic acid: comparative analysis of three carriers,in vitro dissolution,antioxidant potential and in vivo anti-platelet effect

This article aimed to improve the relative solubility and dissolution rate of ferulic acid (FA) by the use of spray-dried solid dispersions (SDs) in order to ensure its in vitro antioxidant potential and to enhance its in vivo anti-platelet effect. These SDs were prepared by spray-drying at 10 and 20% of drug concentration using polyvinylpyrrolidone K30 (PVP-K30), polyethylene glycol 6000 (PEG 6000) and poloxamer-188 (PLX-188) as carriers. SDs and physical mixtures (PM) were characterized by SEM, XRPD, FTIR spectroscopy and TGA analysis. Spray-dried SDs containing FA were successfully obtained. Relative solubility of FA was improved with increasing carrier concentration. PVP-K30 and PEG 6000 formulations showed suitable drug content values close to 100%, whereas PLX-188 presented mean values between 70 and 90%. Agglomerates were observed depending on the carrier used. XRPD patterns and thermograms indicated that spray-drying led to drug amorphization and provided appropriate thermal stability, respectively. FTIR spectra demonstrated no remarkable interaction between carrier and drug for PEG 6000 and PLX-188 SDs. PVP-K30 formulations had changes in FTIR spectra, which denoted intermolecular O–H???O?=?C bonds. Spray-dried SDs played an important role in enhancing dissolution rate of FA when compared to pure drug. The free radical-scavenging assay confirmed that the antioxidant activity of PEG 6000 10% SDs was kept. This formulation also provided a statistically increased in vivo anti-platelet effect compared to pure drug. In summary, these formulations enhanced relative solubility and dissolution rate of FA and chosen formulation demonstrated suitable in vitro antioxidant activity and improved in vivo anti-platelet effect.     

The Kinetics of Drug Release from Ethylcellulose Solid Dispersions

Abstract

Sulphadiazine - ethylcellulose (EC) solid dispersions with different drug: carrier ratios were prepared and fractionated. In vitro drug release followed an apparent zero-order kinetics rate constant being dependent on the thickness of the coat which was the rate controlling step in the process. Drug release was found to increase as the granule size was decreased. The amount of drug released was found to be pH dependent thus showing the existence of pores in the coat surrounding the drug particles. Inclusion of polyethylene glycol or sodium lauryl sulphate in the coat material or dissolution medium resulted in increased dissolution, an effect which was attributed to increase in porosity, reduction of interfacial tension and increase in wettability which was associated with the presence of these compounds.     

Characterization of ibuproxam binary and ternary dispersions with hydrophilic carriers

This work investigates the possibility of increasing the dissolution properties of ibuproxam (a poorly water-soluble anti-inflammatory drug) using hydrophilic carriers such as polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), or urea, alone or in combination. Phase-solubility studies showed that the carrier solubilizing power was in the order PEG>PVP>urea and evidenced a synergistic effect in drug solubility improvement when using carrier combinations. Binary and ternary systems, at 20/80 or 20/40/40 (w/w) drug/carrier(s) ratios, prepared by coevaporation of their ethanolic solutions or by cogrinding physical mixtures in a high-energy vibrational micromill, were characterized by differential scanning calorimetry (DSC), hot stage microscopy (HSM), and scanning electron microscopy (SEM) analyses. The results of dissolution tests (USP paddle method), in terms of Dissolution Efficiency, indicated that ternary systems were up to 35% more effective than the corresponding binary preparations and coevaporated products were up to 45% more efficacious than the corresponding coground ones. The IBUX-PEG-PVP coevaporated was the best product, allowing a more than three-times increase in Dissolution Efficiency with respect to drug alone; moreover, t50% (> 60 min for pure ibuproxam) was < 10 min, and 90% dissolution was achieved after 30 min, whereas only 40% was obtained after 60 min for pure drug. The best performance of this system was attributed to a joined effect of the strong amorphizing power of PVP (as demonstrated by solid state analyses) with the high solubilizing efficacy of PEG (as emerged from phase-solubility studies). The drug dissolution rate from solid dispersions remained practically unchanged after one-year storage at room temperature in closed containers.     

Chitosan microparticles: influence of the gelation process on the release profile and oral bioavailability of albendazole,a class II compound

Encapsulation of albendazole, a class II compound, into polymeric microparticles based on chitosan-sodium lauryl sulfate was investigated as a strategy to improve drug dissolution and oral bioavailability. The microparticles were prepared by spray drying technique and further characterized by means of X-ray powder diffractometry, infrared spectroscopy and scanning electron microscopy. The formation of a novel polymeric structure between chitosan and sodium lauryl sulfate, after the internal or external gelation process, was observed by infrared spectroscopy. The efficiency of encapsulation was found to be between 60 and 85% depending on the internal or external gelation process. Almost spherically spray dried microparticles were observed using scanning electron microscopy. In vitro dissolution results indicated that the microparticles prepared by internal gelation released 8% of the drug within 30?min, while the microparticles prepared by external gelation released 67% within 30?min. It was observed that the AUC and C_max values of ABZ from microparticles were greatly improved, in comparison with the non-encapsulated drug. In conclusion, the release properties and oral bioavailability of albendazole were greatly improved by using spraydried chitosan-sodium lauryl sulphate microparticles.     

Physical,Chemical, and Bioavailability Studies of Parenteral Diazepam Formulations Containing Propylene Glycol and Polyethylene Glycol 400

Abstract

Parenteral diazepam formulations (10 mg/ml), XXV and XXX were prepared using propylene glycol and/or polyethylene glycol 400. The viscosity of formulations XXV and XXX was found to be 9.72 and 11.13 Cps., respectively using Stormer viscosimeter at 22° C. The accelerated stability studies indicated shelf-life of formulations XXV and XXX to be 132     

Enhanced dissolution and absorption of trimethoprim from coprecipitates with polyethylene glycols and polyvinylpyrrolidone

Coprecipitates of trimethoprim have been prepared by solvent method using polyethylene glycols 4000, 6000 and 9000, and polyvinylpyrrolidone (M.W. 40,000) as water soluble carriers. A marked increase in the dissolution rate of trimethoprim in the coprecipitates was observed compared with that of the drug alone. Coprecipitates with polyethylene glycol 6000 (1:2) showed faster release as well as bioavailability of the drug in human volunteers.     

Studies on solid dispersions of nifedipine

Abstract

Nifedipine-Polyethylene glycol solid dispersions were prepared by melting or fusion method in order to improve nifedipine solubility in the aqueous body fluids. The dissolution rate of the drug was markedly increased in these solid dispersion systems. The increase in dissolution was a function of the ratio of drug to polyethylene glycol used and the molecular weight of polyethylene glycol. The dissolution rate was compared with a 10% w/w physical mixture of drug with polyethylene glycol.

The physical state of nifedipine after fusion was determined by X-ray crystallography on the pure drug and on the solidified melts. The X-ray diffraction studies indicated that nifedipine in the solid dispersion which was obtained by sudden cooling of the melt, was in the thermodynamically unstable metastable form. It was established that the slow cooling of the melt as well as powdering of solid dispersion resulted in the emergence of crystallinity.

The effect of aging on nifedipine-polyethylene glycol 6000 solid dispersions has been investigated. After storage at room temperature for six months, solid dispersions showed no change in the dissolution rate and the X-ray diffraction pattern showed slight enhancement in crystallinity.