Properties of Solid Dispersions of Naproxen in Various Polyethylene Glycols

Abstract

Solid dispersions of naproxen in polyethylene glycol 4000, 6000, and 20000, aimed at improving the drug dissolution characteristics, were prepared by both the solvent and melting methods. The drug-polymer interaction in the solid state was investigated using differential scanning calorimetry, hot-stage microscopy, Fourier-transform infrared spectroscopy, and x-ray diffraction analysis. Interaction in solution was studied by phase solubility analysis and dissolution experiments. Computer-aided molecular modeling was used to supplement the results from phase solubility studies. No important chemical interaction was found between naproxen and polyethylene glycol, either in solution or in the solid state, apart from the formation of weak drug-polymer hydrogen bonds. The increase of naproxen dissolution rate from its binary systems with polyethylene glycol could be attributed to several factors such as improved wettability, local solubilization, and drug particle size reduction. No influence of polymer molecular weight or of the solid dispersion preparation method on drug dissolution properties was found.     

Thermal Behavior and Dissolution Properties of Naproxen From Binary and Ternary Solid Dispersions

Solid dispersions of 10% w/w naproxen (NAP) in poly(ethylene glycol) (PEG) (4000, 6000, or 20,000) as a carrier with or without incorporation of anionic (sodium dodecyl sulfate; SDS) or nonionic (Tween 80; Tw80) surfactant were prepared by the melting method. Physicochemical characteristics were determined by differential scanning calorimetry (DSC) and X-ray diffraction analysis. The results of dissolution studies showed that drug dissolution properties were better from ternary systems than from binary systems since in the former the wetting and solubilizing effects of surfactant and polymer were additive. No influence of the PEG molecular weight was found. The best performance given by anionic surfactant has been attributed to several factors, such as higher hydrophilicity, better solubilizing power, and most facile interaction with both drug and PEG. No important changes in solid-state characteristics or in drug dissolution properties were found after 30 months storage for dispersions with or without surfactant. Only a slight decrease in initial drug dissolution rate was observed at the highest concentration (10% w/w) of SDS.     

Preformulation Studies on Solid Dispersions Containing Triamterene or Temazepam in Polyethylene Glycols or Gelucire 44/14 for Liquid Filling of Hard Gelatin Capsules

Abstract

Solid dispersions of triamterene or temazepam in polyethylene glycols or gelucire 44/14 have been investigated. The phase equilibria of the drugs and carriers were determined by Differential Thermal Analysis and Hot Stage Microscopy. Particle Size Analysis was carried out using double image microscopy, whilst phase solubility techniques and dissolution methods were used to study solubility, dissolution and ageing.

It has been shown that triamterene forms monotectics with polyethylene glycols and gelucire 44/14 and temzepam shows partial solubility. The effect of the carriers on particle size depends on the solubility of the drug in the carrier and size reduction is observed where the drug is soluble in the carrier.     

Preformulation Studies on Solid Dispersions Containing Triamterene or Temazepam in Polyethylene Glycols or Gelucire 44/14 for Liquid Filling of Hard Gelatin Capsules

Solid dispersions of triamterene or temazepam in polyethylene glycols or gelucire 44/14 have been investigated. The phase equilibria of the drugs and carriers were determined by Differential Thermal Analysis and Hot Stage Microscopy. Particle Size Analysis was carried out using double image microscopy, whilst phase solubility techniques and dissolution methods were used to study solubility, dissolution and ageing.

It has been shown that triamterene forms monotectics with polyethylene glycols and gelucire 44/14 and temzepam shows partial solubility. The effect of the carriers on particle size depends on the solubility of the drug in the carrier and size reduction is observed where the drug is soluble in the carrier.     

Stability and Dissolution Rates of Corticosteroids in Polyethylene Glycol Solid Dispersions

A study has been made to examine the stability and dissolution rates of prednisolone, prednisone and hydrocortisone formulated as solid dispersions in polyethylene glycols. Of the five PEG samples used, three enhanced the chemical instability of the steroids; the effect being dependent on the PEG sample and storage conditions of the solid dispersions. Dissolution rates of the steroids were relatively fast from the solid dispersions and showed no significant changes upon storage. Using two methods of analysis (direct UV spectrophotometry and the USP blue tetrazolium method), it is concluded that the chemical instability of the steroids in some PEG samples was due to alterations in the dihydroxy acetone side chain. One of the decomposition products found appeared to be an acidic compound resulting from oxidation of the C₁₇ side chain. The oxidation is presumably accelerated by a peroxide impurity in PEG samples.     

Stability and Dissolution Rates of Corticosteroids in Polyethylene Glycol Solid Dispersions

Abstract

A study has been made to examine the stability and dissolution rates of prednisolone, prednisone and hydrocortisone formulated as solid dispersions in polyethylene glycols. Of the five PEG samples used, three enhanced the chemical instability of the steroids; the effect being dependent on the PEG sample and storage conditions of the solid dispersions. Dissolution rates of the steroids were relatively fast from the solid dispersions and showed no significant changes upon storage. Using two methods of analysis (direct UV spectrophotometry and the USP blue tetrazolium method), it is concluded that the chemical instability of the steroids in some PEG samples was due to alterations in the dihydroxy acetone side chain. One of the decomposition products found appeared to be an acidic compound resulting from oxidation of the C₁₇ side chain. The oxidation is presumably accelerated by a peroxide impurity in PEG samples.     

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).     

Retardation of Polymeric Carrier Dissolution by Dispersed Drugs: Factors Influencing the Dissolution of Solid Dispersions Containing Polyethlene Glycols

Molecular weight is an important determinant of plyethylene glycol (PEG) dissolution rate: the rate decreasing as the molecular weight is increased. PEG samples of equivalent nominal. molecular weight had different dissolution properties. Intrinsic viscosity and differential scanning calorimetry suggested that the observed differences my be related to molecular weight variation between samples. The dissolution rate of PEG from solid dispersions is retarded, the effect being dependent on the chemical nature of the drug and its concentration. Phenobarbitone was particularly potent in retarding PEG dissolution. Phenobarbitone dissolution rate was retarded from dispersions of high phenobarbitone content. However drug dissolution from solid dispersions low in phenobarbitone were greater than that of pure phenobarbitone. The low dissolution rates were explained in terms of formation of the 2:1 PEG monomer: phenobarbitone complex during solid dispersion formation. At high PEG weight fractions (i.e. 30:1, 50:1) drug dissolution was carrier controlled and although PEG dissolution was greatly suppressed, it was sufficiently large to transport the drug into solution at a rate greater than that of pure phenobarbitone.     

Retardation of Polymeric Carrier Dissolution by Dispersed Drugs: Factors Influencing the Dissolution of Solid Dispersions Containing Polyethlene Glycols

Molecular weight is an important determinant of plyethylene glycol (PEG) dissolution rate: the rate decreasing as the molecular weight is increased. PEG samples of equivalent nominal. molecular weight had different dissolution properties. Intrinsic viscosity and differential scanning calorimetry suggested that the observed differences my be related to molecular weight variation between samples. The dissolution rate of PEG from solid dispersions is retarded, the effect being dependent on the chemical nature of the drug and its concentration. Phenobarbitone was particularly potent in retarding PEG dissolution. Phenobarbitone dissolution rate was retarded from dispersions of high phenobarbitone content. However drug dissolution from solid dispersions low in phenobarbitone were greater than that of pure phenobarbitone. The low dissolution rates were explained in terms of formation of the 2:1 PEG monomer: phenobarbitone complex during solid dispersion formation. At high PEG weight fractions (i.e. 30:1, 50:1) drug dissolution was carrier controlled and although PEG dissolution was greatly suppressed, it was sufficiently large to transport the drug into solution at a rate greater than that of pure phenobarbitone.     

Carbamazepine and Polyethylene Glycol Solid Dispersions: Preparation, in Vitro Dissolution, and Characterization

The objective of this study was to prepare solid dispersions of carbamazepine (CBZ) using polyethylene glycol (PEG) 4000 and PEG 6000, measure the dissolution, and characterize using x-ray diffraction, DSC, and IR spectroscopy. Solid dispersions were prepared by either the melt or solvent methods. A comparison of dissolution profiles of the solid dispersions indicated dramatic increases in the rate and extent of CBZ dissolution from solid dispersions. The dissolution of physical mixtures provided evidence of the solubilizing effects of PEGs. Untreated CBZ exhibited 10.09 ± 2.92% dissolution in 10 min (D_l0); whereas, a melt of PEG 6000 and CBZ at a ratio of 6: 1 provided 36.49 ± 1.97% and a melt of PEG 4000 and CBZ at a ratio of 6: 1 gave a D₁₀ of 23.59 ± 1.45%. The rate and extent of dissolution of CBZ were significantly higher when blends of the PEGs were employed to prepare solid dispersion. The melt method provided significantly higher rate and extent of dissolution of CBZ than the solvent method. Also, the rate and extent of dissolution of CBZ were significantly greater when the solid dispersion was cooled at room temperature as opposed to with ice (faster). X-ray diffractometry revealed almost a complete loss of crystallinity of CBZ in solid dispersions. IR spectrometry indicated an increase in amorphocity of the PEGs after melting. IR spectra suggested that no complexation occurred between the PEGs and CBZ. Alterations in the crystallinity of the system were also supported by the DSC thermograms. Decreasing heats of fusion implied decrease in crystallinity, which would be expected to provide greater dissolution rates. Peak melting temperatures obtained from the thermograms ruled out the possibility of the formation of a eutectic mixture. However, the formation of solid solution could also be a possible mechanism for the increase in dissolution.     

Carbamazepine and Polyethylene Glycol Solid Dispersions: Preparation,in Vitro Dissolution,and Characterization

Abstract

The objective of this study was to prepare solid dispersions of carbamazepine (CBZ) using polyethylene glycol (PEG) 4000 and PEG 6000, measure the dissolution, and characterize using x-ray diffraction, DSC, and IR spectroscopy. Solid dispersions were prepared by either the melt or solvent methods. A comparison of dissolution profiles of the solid dispersions indicated dramatic increases in the rate and extent of CBZ dissolution from solid dispersions. The dissolution of physical mixtures provided evidence of the solubilizing effects of PEGs. Untreated CBZ exhibited 10.09 ± 2.92% dissolution in 10 min (D_l0); whereas, a melt of PEG 6000 and CBZ at a ratio of 6: 1 provided 36.49 ± 1.97% and a melt of PEG 4000 and CBZ at a ratio of 6: 1 gave a D₁₀ of 23.59 ± 1.45%. The rate and extent of dissolution of CBZ were significantly higher when blends of the PEGs were employed to prepare solid dispersion. The melt method provided significantly higher rate and extent of dissolution of CBZ than the solvent method. Also, the rate and extent of dissolution of CBZ were significantly greater when the solid dispersion was cooled at room temperature as opposed to with ice (faster). X-ray diffractometry revealed almost a complete loss of crystallinity of CBZ in solid dispersions. IR spectrometry indicated an increase in amorphocity of the PEGs after melting. IR spectra suggested that no complexation occurred between the PEGs and CBZ. Alterations in the crystallinity of the system were also supported by the DSC thermograms. Decreasing heats of fusion implied decrease in crystallinity, which would be expected to provide greater dissolution rates. Peak melting temperatures obtained from the thermograms ruled out the possibility of the formation of a eutectic mixture. However, the formation of solid solution could also be a possible mechanism for the increase in dissolution.     

Enhancement of Dissolution of Ethopropazine Using Solid Dispersions Prepared with Phospholipid and/or Polyethylene Glycol

The purpose of this study was to improve the dissolution properties of a poorly water soluble and bioavailable drug, ethopropazine HCl (ET), by incorporating the drug in three different types of solid dispersion systems. Solid dispersions of ET were prepared using 1:1 (w/w) ratios of (1) phospholipid (1,2 dimyristoyl-sn-glycerophosphocholine) (DMPC), (2) polyethylene glycol 8000 (PEG8000), and (3) a novel combination of both DMPC and PEG8000. Using the solvent method of preparation, ET and DMPC and/or PEG were dissolved in chloroform, and solvent subsequently was evaporated using nitrogen gas. The resulting solid dispersion(s) was passed through a 60-mesh sieve. Characterization of ET/DMPC solid dispersion was performed by differential scanning calorimetry (DSC) and X-ray diffractometry studies. Dissolution studies conducted in phosphate buffered saline (PBS) (pH 7.4, 37°C ± 0.5°C) using the USP type II (paddle) dissolution apparatus showed significant increases in the dissolution rate of ET with all the solid dispersions in this study. Specifically, within the first 5 min (D5), solid dispersions containing ET/DMPC (1:1) showed an eightfold increase in dissolution; in combination with DMPC and PEG8000 (1:1), there was an approximately sixfold increase; and a fourfold increase was observed with PEG8000 (1:1). Complete dissolution of all solid dispersions occurred within 60 min (D60) of the run. Storage of the ET/DMPC sample for over 4.5 months revealed a decrease in the dissolution rate when compared to freshly prepared sample. Overall, it was concluded that the dissolution rate of ET significantly improved when dispersed in all the selected carrier systems. However, the solid dispersion of ET/DMPC was observed to be superior to the other combinations used.     

Enhancement of Dissolution of Ethopropazine Using Solid Dispersions Prepared with Phospholipid and/or Polyethylene Glycol

The purpose of this study was to improve the dissolution properties of a poorly water soluble and bioavailable drug, ethopropazine HCl (ET), by incorporating the drug in three different types of solid dispersion systems. Solid dispersions of ET were prepared using 1:1 (w/w) ratios of (1) phospholipid (1,2 dimyristoyl-sn-glycerophosphocholine) (DMPC), (2) polyethylene glycol 8000 (PEG8000), and (3) a novel combination of both DMPC and PEG8000. Using the solvent method of preparation, ET and DMPC and/or PEG were dissolved in chloroform, and solvent subsequently was evaporated using nitrogen gas. The resulting solid dispersion(s) was passed through a 60-mesh sieve. Characterization of ET/DMPC solid dispersion was performed by differential scanning calorimetry (DSC) and X-ray diffractometry studies. Dissolution studies conducted in phosphate buffered saline (PBS) (pH 7.4, 37°C ± 0.5°C) using the USP type II (paddle) dissolution apparatus showed significant increases in the dissolution rate of ET with all the solid dispersions in this study. Specifically, within the first 5 min (D5), solid dispersions containing ET/DMPC (1:1) showed an eightfold increase in dissolution; in combination with DMPC and PEG8000 (1:1), there was an approximately sixfold increase; and a fourfold increase was observed with PEG8000 (1:1). Complete dissolution of all solid dispersions occurred within 60 min (D60) of the run. Storage of the ET/DMPC sample for over 4.5 months revealed a decrease in the dissolution rate when compared to freshly prepared sample. Overall, it was concluded that the dissolution rate of ET significantly improved when dispersed in all the selected carrier systems. However, the solid dispersion of ET/DMPC was observed to be superior to the other combinations used.     

Pharmacokinetics of Sulfisoxazole Solid Dispersions in Rabbis

Abstract

The approach of solid dispersion was found useful for optimizing the pharmacokinetics of sulfisoxazole in Rabbits. This was illustrated on the example of bicomponent solid dispersions containing water-soluble, urea and pvp 25000, and water insoluble, DCA and GMS, carriers. The effect of the type and concentration of the inert carrier was investigated and found to influence the pharmacokinetic parameters studied to different extents. The multicomponent (Tri and quaternary) solid dispersions implied different effects on the pharmacokinetics of sulfisoxazole according to the nature and the proportion of the carrier used. Dispersing sulfisoxazole in the solid state in innert carriers such as GMS, DCA, urea and PVP was shown to influence significantly the dissolution rate of the drug to different extents. Dispersion of sulfisoxazole in soluble carriers resulted in significant enhancement of the dissolution rate whatever the equipment used. Correlation of sulfisoxazole in-vitro dissolution rate parameters, D.E. and t_75%, to the pharmacokinetic parameters revealed no or very poor correlation.However, the t_75% parameter by the USP disintegration tester may be considered to exhibit the most reasonable correlation to the pharmacokinetic parameter K_e.     

Pharmacokinetics of Sulfisoxazole Solid Dispersions in Rabbis

The approach of solid dispersion was found useful for optimizing the pharmacokinetics of sulfisoxazole in Rabbits. This was illustrated on the example of bicomponent solid dispersions containing water-soluble, urea and pvp 25000, and water insoluble, DCA and GMS, carriers. The effect of the type and concentration of the inert carrier was investigated and found to influence the pharmacokinetic parameters studied to different extents. The multicomponent (Tri and quaternary) solid dispersions implied different effects on the pharmacokinetics of sulfisoxazole according to the nature and the proportion of the carrier used. Dispersing sulfisoxazole in the solid state in innert carriers such as GMS, DCA, urea and PVP was shown to influence significantly the dissolution rate of the drug to different extents. Dispersion of sulfisoxazole in soluble carriers resulted in significant enhancement of the dissolution rate whatever the equipment used. Correlation of sulfisoxazole in-vitro dissolution rate parameters, D.E. and t_75%, to the pharmacokinetic parameters revealed no or very poor correlation.However, the t_75% parameter by the USP disintegration tester may be considered to exhibit the most reasonable correlation to the pharmacokinetic parameter K_e.     

Evaluation of Solid Dispersions of Clofazimine

ABSTRACT

Clofazimine (CLF) was formulated with polyethylene glycol (PEG) and polyvinyl pyrrolidone (PVP) as a solid solid dispersion (SSD) to increase the aqueous solubility and dissolution rate of the drug. Different molecular weights of PEG (1500, 4000, 6000, and 9000 Da) and PVP (14,000 and 44,000 Da) were used in different drug:carrier weight ratios (1:1, 1:5, and 1:9) and their effect on the dissolution performance of the drug was evaluated in USP Type 2 apparatus using 0.1 N HCl medium. The dissolution rate was compared with corresponding physical mixtures, a currently marketed soft gelatin capsule product, and free CLF. The effect of different methods of preparation (solvent/melt) on the dissolution rate of CLF was evaluated for PEG solid dispersions. Saturation solubility and phase solubility studies were carried out to indicate drug:carrier interactions in liquid state. Infrared (IR) spectroscopy and X-ray diffraction (XRD) were used to indicate drug:carrier interactions in solid state. Improvement in the drug dissolution rate was observed in solid dispersion formulations as compared to the physical mixtures. The dissolution rate improved with the decreasing weight fraction of the drug in the formulation. Polyvinyl pyrrolidone solid dispersion systems gave a better drug release profile as compared to the corresponding PEG solid dispersions. The effect of molecular weight of the PEG polymers did not follow a definite trend, while PVP 14,000 gave a better dissolution profile as compared to PVP 44,000. Improvement in saturation solubility of the drug in the solid dispersion systems was noted in all cases. Further, IR spectroscopy indicated drug:carrier interactions in solid state in one case and XRD indicated reduction in the crystallinity of CLF in another. It was concluded that solid-dispersion formulations of Clofazimine can be used to design a solid dosage form of the drug, which would have significant advantages over the currently marketed soft gelatin capsule dosage form.     

Dissolution Behavior of Griseofulvin Solid Dispersions Using Polyethylene Glycol, Talc, and Their Combination as Dispersion Carriers

Griseofulvin solid dispersions were prepared using polyethylene glycol 6000 (PEG), talc, and their combination as carriers by the solvent method. The dissolution of griseofulvin from these dispersions was studied. It was found that in these carriers the drug dissolution rate was a function of drug loading. The dissolution rate from dispersions prepared using PEG was similar to that from PEG/talc dispersions, especially at a low percentage of drug loading. Dispersions of PEG and PEG/talc provided dissolution rates faster than those from dispersions of talc. The incorporation of talc in PEG yielded dispersions with properties of less tackiness and ease for handling. Dissolution kinetics, based on the Hixson-Crowell equation, was used to determine the characteristics of griseofulvin particles in dispersions. Linear relationships were obtained for PEG and PEG/talc dispersions that indicated the presence of a uniformly sized monoparticulate system, whereas deviation from linearity was observed for talc dispersions. This appeared to be a multiparticulate system in which particles were present as free form and adsorbed form on the surface of talc.     

Dissolution Profiles of Flurbiprofen in Phospholipid Solid Dispersions

Abstract

This study is concerned with the development of a solid dispersion formulation of flurbiprofen (FLP) and phospholipid (PL) with improved dissolution characteristics. The FLP powders were blended with PL to produce FLP-PL physical mixtures or made into solid dispersions with PL by the solvent method. The FLP exhibited significantly improved dissolution rates in PL coprecipitate (coppt) compared to the physical mixtures or FLP alone. The dissolution studies suggested that less than a 20:1 ratio of FLP to PL was required to disperse FLP completely in the carrier. The coppt yielded a ninefold greater initial dissolution rate. Also, the total amount dissolved after 60 min was twofold greater at a 10:1 ratio of FLP to L-(-dimyristoyl phosphatidylglycerol (DMPG). Similar results were observed with a ratio as tow as 20:1 (FLP:DMPG). Increasing the DMPG content did not increase the rate to any significant extent. Thus, a small PL:FLP ratio improved the dissolution to a significant level. Thus, an FLP:PL dispersion may have the clinical advantages of quick release and excellent bioavailability.     

Implications of Peroxide Formation in Lotion and Ointment Dosage Forms Containing Polyethylene Glycols

The influence of various factors on the formation rate of peroxide-like impurities in polyethylene glycols was studied. Conditions of high temperature and agitation increased this rate. Varying formation rates were found with glycols from different manufacturers and this seemed to be related to the initial level of peroxide impurity. Aged samples generated peroxides at a faster rate than glycols recently acquired from a manufacturer. Peroxides were an intermediata in the degradation of glycols to carboxylic acids. It is suggested that an atmosphere of nitrogen be used when solubilizing drugs in glycols at high temperatures. The mixing of polyethylene glycol 1500 at 70° with white petrolatum, resulted in a rapid decrease in peroxide content in the glycol and improved the stability of oxidizable drugs in ointment formulations containing glycol and petrolatum.     

Mechanisms of Dissolution of Fast Release Solid Dispersions

Abstract

Drug dissolution from a solid dispersion is dependent on the technology employed to prepare the dispersion and on the proportion and properties of the carrier used. The diffusion models describing dissolution from multi-component solids seem to adequately describe drug release from non-disintegrating systems in the weight fraction range where the drug phase is expected to control dissolution. When solid dispersions have higher dissolution rates than corresponding mechanical mixtures, solid state changes during the formation of the dispersion are indicated. These increases in rate may result from the formation of higher energy phases of either component or from interactions between the components. The carrier may play an important role in the formation of these phases and in stabilizing them during subsequent dissolution. When a large relative solubility difference exists between the carrier and the drug, deviations from theory can be expected to occur at high carrier weight fractions. The model fails because insufficient drug phase is present to form a viable surface drug layer. Drug release then becomes controlled by dissolution of the carrier. In polymer based systems the presence of drug retards dissolution of the carrier, possibly through effects on binding and polymer swelling. These effects need to be quantified in order to allow prediction of drug release from high carrier weight fraction systems.