AGGREGATION DURING THE DISSOLUTION OF DIAZEPAM IN INTERACTIVE MIXTURES

ABSTRACT

The dissolution of micronized diazepam (1.0-10.0%) in interactive mixtures with lactose-povidone, Emdex®, TabBase® and Compactrol® as carriers was investigated using the USP paddle method and distilled water as the dissolution medium. Dissolution rate of the binary diazepam-carrier mixtures increased using more soluble carriers such as lactose-povidone and decreased as the diazepam concentration of the mixtures increased. The data were interpreted by considering dissolution from both dispersed and aggregated particles and modelled using monoexponential and biexponential equations allowing the estimation of reciprocal dissolution rate constants for dispersed and aggregated particles (k_d and k_a and initial aggregate concentrations (C_a). The estimated k_d parameters were independent of carrier and diazepam concentration while the ka. parameters varied and were dependent on the aggregate size distribution in the interactive mixtures studied. The degree of aggregation increased markedly with increasing diazepam concentration and was greatest for the less soluble carrier, Compactrol®. Ternary surfactant interactive mixtures containing diazepam and sodium lauryl sulphate (100:2) adhered to the carrier surface were developed and demonstrated improved dissolution rates which were attributed to the deaggregation effect of the surfactant in the aggregate microenvironment. The effect was most noticeable at 10 percent drug loadings where the surfactant concentration was greatest and where both the k_a and C_a parameters were minimized.     

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.     

Dissolution, Bioavailability and Ulcerogenic Studies on Solid Dispersions of Indomethacin in Water Soluble Cellulose Polymers

The dissolution rate, bioavailability and ulcerogenic activity of indomethacin dispersed in water soluble cellulose polymers was investigated. Solid dispersions of indomethacin in hydroxypropyl cellulose-SL (HPC-SL), hydroxypropylmethyl cellulose (HPMC) and hydroxyethyl cellulose (HEC) were prepared by common solvent method with a view to improve its dissolution and absorption characteristics. The dispersions were evaluated by X-ray diffraction, TLC, IR, dissolution rate, bioavailability and ulcerogenic studies. TLC and IR studies indicated no interaction between indomethacin and carriers. Indomethacin in the dispersions was found to be in amorphous form. Marked increase in the dissolution rate and efficiency of indomethacin was observed in the case of solid dispersions. HPC-SL gave the highest dissolution improvement. A 30-fold increase in dissolution was observed with indomethacin-HPC-SL (9:1) dispersion.

In vivo studies in human subjects showed a significant increase in absorption rate (k_a) and serum levels of indomethacin with solid dispersions when compared to indomethacin alone. However, the extent of bioavailabilty was the same with both indomethacin and its solid dispersions. About 70-80 per cent reduction in ulcerogenic activity was observed with solid dispersions and the dispersions were found to have negligible ulcerogenic activity.     

Dissolution from ordered mixtures: The effect of stirring rate and particle characteristics on the dissolution rate.

Different particle size fractions of three carriers were used to prepare ordered mixtures of frusemide. The dissolution of these mixtures were compared with a frusemide suspension and pure frusemide agglomerates by the USP XXI paddle method at three rotational speeds.

The dissolution of mixtures containing a highly soluble carrier (sodium chloride) were comparable to the suspension depending on the particle size of the carrier. Insoluble carriers (dicalciumphosphatedihydrate and microcrystalline cellulose) increased the dissolution, but the enhancement depended on the rotational speed, the particle size and the density of the carrier.     

Transdermal delivery of propranolol using mixed grades of Eudragit: design and in vitro and in vivo evaluation

A matrix-dispersion-type transdermal drug delivery system of propranol was developed using different ratios of mixed polymeric grades of Eudragit. Formulations were evaluated for in vitro dissolution characteristics using a Cygnus' sandwich patch holder. Selected formulations followed zero-order release kinetics. In vivo evaluation was carried out on healthy human volunteers following a balanced incomplete block design (BIBD). In vitro dissolution rate constant k and pharmacokinetic parameters generated from plasma and urine were evaluated statistically. Statistically excellent correlation was found between percentages of drug absorbed from patch versus C_max, AUC_0-24, and AUC_0-∞. A highly significant difference was observed when C_max and AUC_0- generated from plasma and urine data were compared, but when k_e, t_1/2e, k_a, t_1/2awere compared, the difference was not significant. Urinary excretion data are suggested as a simpler alternative to blood-level data in studying the kinetics of absorption and deriving the absorption parameter.     

Influence of selected water soluble carbohydrates on the dissolution profile of prednisolone

The utilization of three water soluble carbohydrates as carrier to improve the dissolution rate of prednisolone was studied. Coprecipitates and physical mixtures of the drug and the carriers in three different proportions were prepared and their dissolution profile was compared with the dissolution profile of the pure drug. The remarkably fast and erratic dissolution of prenisolone observed from the coprecipitates was possible due to the conversion of prednisolone into its metastable or amorphous form durning the coprecipitation process. The dissolution rate of the drug from the physical mixtures was much higher than from the pure drug itself. Effect of aging of the coprecipitate on the dissolution profile showed an increasing tendency of the dissolution curve to match with that of the corresponding physical mixture.     

Dissolution Characteristics of Interactive Powder Mixtures. Part One: Effect of Solubility and Particle Size of Excipients

Abstract

Interactive mixtures of fine cohesive drug powders and coarse free flowing excipients are reported to increase dissolution rates of poorly soluble drugs. However, dissolution rates are known to be affected by the solubility characteristics of the excipients as well as excipients surface characteristics after mixing with lubricant.

In this study the effects of solubility and particle size of excipients on dissolution of micronized griseofulvin from interactive powder mixtures were investigated. Quantitative assessment of dissolution from such mixtures showed that systems containing soluble excipients increased dissolution of the drug more efficiently than mixtures prepared using insoluble excipients. The role of the soluble excipient was more significant after mixing with magnesium stearate. Excipients of smaller particle sizes increased dissolution more efficiently than their large size counterparts. Effects of particle size were particularly significant in case of water insoluble excipients.     

Influence of selected water soluble carbohydrates on the dissolution profile of prednisolone

Abstract

The utilization of three water soluble carbohydrates as carrier to improve the dissolution rate of prednisolone was studied. Coprecipitates and physical mixtures of the drug and the carriers in three different proportions were prepared and their dissolution profile was compared with the dissolution profile of the pure drug. The remarkably fast and erratic dissolution of prenisolone observed from the coprecipitates was possible due to the conversion of prednisolone into its metastable or amorphous form durning the coprecipitation process. The dissolution rate of the drug from the physical mixtures was much higher than from the pure drug itself. Effect of aging of the coprecipitate on the dissolution profile showed an increasing tendency of the dissolution curve to match with that of the corresponding physical mixture.     

Some Properties of Diazepam-Polyethylene Glycol 6000 Solid Dispersions and their Modification in the Presence of Stearic Acid of Polysorbate 80

Abstract

Physical mixtures and melts of diazepam and polyethylene glycol 6000 (PEG 6000) have been studied by Differential Scanning Calorimetry (DSC) and Differential Thermal Analysis (DTA). Problems were encountered in determining the precise position of the eutectic which contained <30% diazepam. Melts contained amorphous diazepam and, immediately after preparation, an unstable form of PEG 6000 which transformed on storage to a more stable form, probably folded crystals. Dissolution rates were determined by constant surface area methodology and were greatest in melts containing 15% diazepam. The inclusion of 1 or 5% polysorbate 80 or 1% stearic acid into the melts slightly increased the dissolution rates from dispersions containing 5, 10 or 15% diazepam but especially from dispersions containing 20% diazepam. A limited 4-week ageing study indicated that age-induced changes depended on both the storage temperature and diazepam concentration. The inclusion of either stearic acid or polysorbate 80 appeared not to protect dissolution rates against ageing     

Solid state and dissolution rate characterization of co-ground mixtures of nifedipine and hydrophilic carriers

Co-ground powders of the poorly water-soluble drug nifedipine and a hydrophilic carrier, [partially hydrolyzed gelatin (PHG), polyvinylpyrrolidone (PVP), sodium dodecyl sulfate (SDS), hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), urea or Pluronic F108] were prepared in order to improve the dissolution rate of nifedipine. The effects of type of grinding equipment, grinding time, and type of hydrophilic carrier on the crystallinity of nifedipine (x-ray diffraction and differential scanning calorimetry) on the interaction between drug and carriers (differential scanning calorimetry), on the particle size and appearance (scanning electron microscopy), on the wettability (contact angle measurements), and on the drug release were investigated. Grinding nifedipine together with these carriers improved the dissolution rate. PHG-ground mixtures resulted in the fastest dissolution rate followed by PVP, SDS, HPMC, Pluronic, urea, and PEG. This effect was not only due to particle size reduction, which increased in the order PHG相似文献   

Preparation of budesonide-poly (ethylene oxide) solid dispersions using supercritical fluid technology

The purpose of this study was to investigate the possibility of preparing solid dispersions of the poorly soluble budesonide by supercritical fluid (SCF) technique, using poly (ethylene oxide) (PEO) as a hydrophilic carrier. The budesonide-PEO solid dispersions were prepared, using supercritical carbon dioxide (SC CO₂) as the processing medium, and characterized by scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), solubility test and dissolution test in order to understand the influence of the SCF process on the physical status of the drug. The endothermic peak of budesonide in the SCF-treated mixtures was significantly reduced, indicating that budesonide was in amorphous form inside the carrier system. This was further confirmed by SEM and PXRD studies. The enhanced dissolution rates of budesonide were observed from SCF-treated budesonide-PEO mixtures. The amorphous characteristic of the budesonide, the better mixing of drug and PEO powders in the presence of SC CO₂, together with the improved wettability of the drug in PEO, produced a remarkable enhancement of the in vitro drug dissolution rate. Thus, budesonide-PEO solid dispersions with enhanced dissolution rate can be prepared using organic solvent-free SCF process.     

Characterization and Dissolution Study of Oxodipine from Solid Binary Systems

Thennomicroscopy and differential scanning calorimetry were employed to characterize solid binary systems prepared with oxodipine and PEG 6000, 2-hydroxypropyl-β-cyclodextrin or mannitol. DSC curves did not allow to diferentiate physical mixtures from solid dispersions. Thennomicroscopy revealed the interactions that can be produced between drug and each carrier, due to heat contribution, when the physical mixtures were observed; also this thermal technique permited us to ascertain the composition of particles that constitute the solid dispersions. Dissolution studies showed that the amelioration obtained in oxodipine dissolution from physical mixtures was due to the dessagregant action of the carriers, which obtained an increase of the drug surface in contact with the dissolution medium. The proportions and carrier nature influence the oxodipine dissolution, fundamentally from solid dispersions, where the interaction drug/carrier is stronger than in physical mixtures.     

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.     

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.     

Interactive Mixture as a Rapid Drug Delivery System

The effectiveness of an interactive mixture as a rapid drug delivery system is compared with that of a solid dispersion. The influences of drug load, particle size, and crystallinity of these test systems are investigated. The interactive mixtures and solid dispersions were prepared from polyethylene glycol (PEG) 3350 and hydrophobic nifedipine drug by means of physical mixing and melting methods, respectively. The formed products were subjected to drug particle size and crystallinity analyses, and dissolution tests. In comparison with the interactive mixtures, the solid dispersions with low drug load were more effective as a rapid drug delivery system, as the size of a given batch of drug particles was markedly reduced by the molten PEG 3350. The rate and extent of drug dissolution were mainly promoted by decreasing effective drug particle size. However, these were lower in the solid dispersions than in the interactive mixtures when a high load of fine drug particles was used as the starting material. This was attributed to drug coarsening during the preparation of the solid dispersion. Unlike solid dispersions, the interactive mixtures could accommodate a high load of fine drug particles without compromising its capacity to enhance the rate and extent of drug dissolution. The interactive mixture is appropriate for use to deliver a fine hydrophobic drug in a formulation requiring a high drug load.     

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.     

Dissolution OP Nalidixic Acid Solid Dispersions 1. Nal-Hydrotropic salts and NAL-Hyrj systems

The effect of solid dispersion techniques on the dissolution rate of nalidixic acid powder was investigated.

The thermodynanic parameters of all tested systems revealed a spontaneous reaction with no complex affinity to the drug.

Hexamine and sodium citrate showed very powerful solubilizing capacity towards NAL powder.

For piperazine citrate in spite of its low interaction with NAL in the aqueous phase, it proved to be efficient carrier in the solid dispersion system. Hyrj 59 caused the greatest enhancement in NAL dissolution rate of all carriers examined. After 5 minutes, the RDR of the four-fold NAL-HyrJ 59 co-precipitate system was 16.5 times the untreated drug.     

Dissolution Rate A Measurement of the Deaggregation of Furosemide Agglomerates During An Interactive Mixing Process

Agglomerates of drug particles must be broken down and single particles attached to the carrier to ensure a completely random interactive mixture. Here it was found that the dissolution rates of samples from interactive mixtures compared to suspended furosemide was an indication of the deaggregation of furosemide agglomerates during an interactive mixing process. Deaggregation depended on the forces generated during mixing and was quicker when a high density carrier such as sodium chloride was used.     

Preparation of a Solid Dispersion by a Dropping Methodto Improve the Rate of Dissolution of Meloxicam

Application of a solid dispersion system is one of the methods used to increase the bioavailability of poorly water-soluble drugs. Adaptation of the dropping method from the chemical industry as a formulation procedure may help the scaling-up process and simplify the formulation of poorly water-soluble compounds. Meloxicam (ME), a nonsteroidal anti-inflammatory drug that is poorly soluble in water, and polyethylene glycol (PEG) 4000, a water-soluble carrier, were formulated by using a dropping method in an attempt to improve the dissolution of ME. Pure ME and physical mixtures and tablets of ME–PEG 4000 (1:3 ratio) were compared as regards their dissolution with samples formulated by the dropping method. The results revealed that the round particles (solid drops) exhibited a higher dissolution rate than those of the physical mixtures, tablets, and pure ME. Self-modeling curve resolution (SMCR) as a chemometric method was used to evaluate X-ray powder diffractometry (XRPD) data. The results demonstrated the presence of a new crystalline phase in the solid dispersion, which can help the fast and quantitative dissolution from the solid drops. The round particles can be adapted to individual therapy by using a distributor.     

Preparation of a solid dispersion by a dropping method to improve the rate of dissolution of meloxicam

Application of a solid dispersion system is one of the methods used to increase the bioavailability of poorly water-soluble drugs. Adaptation of the dropping method from the chemical industry as a formulation procedure may help the scaling-up process and simplify the formulation of poorly water-soluble compounds. Meloxicam (ME), a nonsteroidal anti-inflammatory drug that is poorly soluble in water, and polyethylene glycol (PEG) 4000, a water-soluble carrier, were formulated by using a dropping method in an attempt to improve the dissolution of ME. Pure ME and physical mixtures and tablets of ME-PEG 4000 (1:3 ratio) were compared as regards their dissolution with samples formulated by the dropping method. The results revealed that the round particles (solid drops) exhibited a higher dissolution rate than those of the physical mixtures, tablets, and pure ME. Self-modeling curve resolution (SMCR) as a chemometric method was used to evaluate X-ray powder diffractometry (XRPD) data. The results demonstrated the presence of a new crystalline phase in the solid dispersion, which can help the fast and quantitative dissolution from the solid drops. The round particles can be adapted to individual therapy by using a distributor.