Chemometric Modelling of Dissolution Rates of Griseofulvin From Solid Dispersions With Polymers

Abstract

The quantitative relationship between the release rate of griseofulvin and the chemical and physical properties of a series of polymers, used for the preparations of solid dispersions, was investigated by the application of multiple regression analysis (MRA), partial least square analysis (PLS) and a new non linear chemometric procedure called CARSO (Computer Aided Response Surface Optimization).

It was confirmed that the degree of crystallinity of griseofulvin and the wettability of the powder samples are important in the dissolution mechanism and in the prediction of dissolution profiles of griseofulvin from these solid dispersions.     

Chemometric Modelling of Dissolution Rates of Griseofulvin From Solid Dispersions With Polymers

The quantitative relationship between the release rate of griseofulvin and the chemical and physical properties of a series of polymers, used for the preparations of solid dispersions, was investigated by the application of multiple regression analysis (MRA), partial least square analysis (PLS) and a new non linear chemometric procedure called CARSO (Computer Aided Response Surface Optimization).

It was confirmed that the degree of crystallinity of griseofulvin and the wettability of the powder samples are important in the dissolution mechanism and in the prediction of dissolution profiles of griseofulvin from these solid dispersions.     

Dissolution Rate Study of Fresh and Aging Triamterene-Urea Solid Dispersions

Triamterene-urea solid dispersions of varying weight fractions were elaborated by the melting carrier method and their dissolution profiles compared with the pure drug and physical mixtures. The dissolution rates of triamterene from solid dispersions were faster than the pure drug and physical mixtures.

Solubility studies revealed a linear increase in the solubility of the triamterene with the increase of urea concentration.

The intrinsic dissolution rates, determined by the rotating disc method, showed linear dissolution profiles in spite of that the scanning electron microscopy examination revealed that the surfaces do not maintain constant during the dissolution process.

Aging of the different preparations for one year at room temperature does not induced significant changes in their dissolution profiles.     

Dissolution Rate Study of Fresh and Aging Triamterene-Urea Solid Dispersions

Triamterene-urea solid dispersions of varying weight fractions were elaborated by the melting carrier method and their dissolution profiles compared with the pure drug and physical mixtures. The dissolution rates of triamterene from solid dispersions were faster than the pure drug and physical mixtures.

Solubility studies revealed a linear increase in the solubility of the triamterene with the increase of urea concentration.

The intrinsic dissolution rates, determined by the rotating disc method, showed linear dissolution profiles in spite of that the scanning electron microscopy examination revealed that the surfaces do not maintain constant during the dissolution process.

Aging of the different preparations for one year at room temperature does not induced significant changes in their dissolution profiles.     

Effervescent Solid Dispersions of Prednisone,Griseofulvin and Primidone

Various prednisone (Pd), griseofulvin (Gr), and primidone (Pr) solid dispersions mady by the fusion method utilizing diffent carriers and drug: carrier ratios were evaluated. Citric acid (CA), succinic acid (SA) and tartaric acid (TA) were employed in various ratios with sodium bicarbonate (SB) as carriers for the respective drugs.

CA:SB was the most effective carrier for releasing Pd and Pr, and SA:SB was found to be the best carrier for Gr. Results showed that there was an increase in in dissolution rate as the proportion of SB increased in the carrier system.     

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.     

The Release Rate of Indomethacin from Solid Dispersions with Eudragite

The coprecipitates were prepared by a solvent technique using Eudragit E as carrier and indomethacin as a model drug.

X-Ray diffractometry, differential scanning calorimetry (DSC) and wettability tests were employed to investigate the physical state of the studied formulations. Up to 50% of indomethacin can be dispersed in an amorphous state in Eudragit E.

The influence of the pH on the in vitro release of solid dispersions has been evaluated. Because of the good solubility of Eudragit E at pH 1.2 a fast dissolution rate of the drug was observed while a marked delay was noticed at pH 7.5 where the polymer is only permeable to water. At pH 5.8 the kinetics of drug release can be modulated by the drug/polymer ratio. The dissolution rate of the drug can be increased by decreasing its amount in the coevaporate.     

The Release Rate of Indomethacin from Solid Dispersions with Eudragite

Abstract

The coprecipitates were prepared by a solvent technique using Eudragit E as carrier and indomethacin as a model drug.

X-Ray diffractometry, differential scanning calorimetry (DSC) and wettability tests were employed to investigate the physical state of the studied formulations. Up to 50% of indomethacin can be dispersed in an amorphous state in Eudragit E.

The influence of the pH on the in vitro release of solid dispersions has been evaluated. Because of the good solubility of Eudragit E at pH 1.2 a fast dissolution rate of the drug was observed while a marked delay was noticed at pH 7.5 where the polymer is only permeable to water. At pH 5.8 the kinetics of drug release can be modulated by the drug/polymer ratio. The dissolution rate of the drug can be increased by decreasing its amount in the coevaporate.     

Solubility and Dissolution of Etoposide from Solid Dispersions of PEG 8000

The Solubility and dissolution of etoposide from solid dispersion of PEG 8000, prepared by the fusion method, were investigated. Stability studies revealed that the etoposide was stable in water for three days at 37 ± 0.5°C alone and as a physical mixture with PEG 8000. However, nearly 5% decomposition was oberved in aqueous solutions made from solid dispersions. TLC, IR and HPLC studies showed both the drug and carrier were stable during the fusion process. Aqueous solubility of etoposide from solid dispersions with etoposide: PEG 8000 ratios of 1:5, 1:10, 1:20, 1:30 and 1:40, was studied at 37 ± 0.5°C, and found to be significantly higher than that of etoposide alone or from its physical mixtures with PEG 8000. These dispersions increased the solubility of etoposide by 32.3%, 96.8%, 133.5%, 280.7% and 326.6% respectively compared to that of etoposide alone, whereas only 1:40 etoposide: PEG 8000 physical mixture demonstrated a significant increase in etoposide solubility (16.1%). Dissolution studies, on the solid dispersions in water at 37 ± 0.5°C, revealed a marked increase in the dissolution rate of etoposide from 1:20, 1:30 and 1:40 solid dispersions with 100% drug dissolving within 1 minute; dissolution time for 1:5 and 1:10 dispersions, and all physical mixtures was 3 minutes while etoposide alone required 30 minutes for complete drug dissolution. The melting behavior of the etoposide-PEG 8000 mixtures and subsequent thermal analysis of the melts suggested that the increase of solubility of etoposide was mostly due to the formation of a solid solution of etoposide in PEG 8000.     

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.     

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.     

顺丁烯二酸酐固相接枝羟乙基纤维素的制备与性能

以N,N-二甲基甲酰胺(DMF)为增塑剂,在无催化剂和溶剂条件下制备了羟乙基纤维素(HEC)和顺丁烯二酸酐(MAH)的酯化产物。通过酸碱滴定法测定酯化率和酯化效率,对酯化反应工艺进行了考察。采用FT-IR表征了产物结构,证明反应主要由MAH酸酐开环和HEC羟基酯化实现,并通过广角X射线衍射(WAXD)和热重分析(TG)对产物进行了进一步研究。结果表明,酯化反应后HEC结晶结构没有明显变化,热稳定性有了较大提高,最大分解温度从268℃提高到300℃左右。     

二氧化碳/环氧丙烷/马来酸酐的三元共聚反应

研究了以负载双金属PBM型为催化剂,通过二氧化碳(CO2),环氧丙烷(PO)与马来酸酐(MA)的三元开环共聚反应,得到一种三元共聚物聚碳酸亚丙酯马来酸酐(PPCMA)。用FT-IR1、H-NMR1、3C-NMR、DSC、WAXD对PPCMA进行了表征。结果表明,成功地引入了马来酸酐单元,且共聚过程中不发生双键交联和构型转化。有效地提高了聚合物的特性粘数[η],玻璃化转变温度Tg以及热稳定性。     

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.     

Characteristics of Bicalutamide Solid Dispersions and Improvement of the Dissolution

ABSTRACT

The purpose of our study was to formulate and evaluate bicalutamide (BL) solid dispersions (SD). The physicochemical properties were evaluated by differential scanning calorimetry (DSC), Fourier-Transform infrared (FT-IR) spectroscopy, Powder X-ray diffractometry (PXRD), dissolution studies, and stability studies. The dissolution studies demonstrated that the dissolution of BL from BL-SD increased with an increase in carrier content (PVP K30). X-ray assays and DSC results both confirmed the amorphous state of BL in BL-SD. Stability studies conducted after 6 months showed that BL exhibited excellent stability in the solid dispersion of PVP K30 (1:5).     

Dissolution of Sulphamethoxazole From Polyethlene Gylcols and Polyvinlpyrrolidone Solid Dispersions

Solid dispersions of sulphamethoxazole have been prepared by fusion and solvent methods using polyethylens glycols 6000 and 9000, and polyvinylpyrrolidone (mol.wt. 40,000) as water-soluble carriers. Coprecipitates with the latter were superior to other carriers in releasing the drug into solution. Melts with the solvent method. Solubility of the drug increased also with the former produced faster rates of dissolution of sulphamethoxazole than the coprecipitate from the solvent method. Solubility of the drug increased also with corresponding increase in the concetrations of these carriers.     

Dissolution of Sulphamethoxazole From Polyethlene Gylcols and Polyvinlpyrrolidone Solid Dispersions

Abstract

Solid dispersions of sulphamethoxazole have been prepared by fusion and solvent methods using polyethylens glycols 6000 and 9000, and polyvinylpyrrolidone (mol.wt. 40,000) as water-soluble carriers. Coprecipitates with the latter were superior to other carriers in releasing the drug into solution. Melts with the solvent method. Solubility of the drug increased also with the former produced faster rates of dissolution of sulphamethoxazole than the coprecipitate from the solvent method. Solubility of the drug increased also with corresponding increase in the concetrations of these carriers.     

Preparation and in Vitro Dissolution Profiles of Tolazamide-Polyethylene Glycol Solid Dispersions

The objective of this study is to prepare solid dispersions of tolazamide (TLZ) using polyethylene glycol (PEG) and measure the dissolution of TLZ. PEG 8000 was used as carrier to prepare solid dispersions by melt and solvent methods. Dissolution studies indicated a remarkable increase in the rate of dissolution of TLZ when dispersed in PEG as well as with physical mixture of TLZ and PEG. The rate of dissolution of TLZ was faster with solid dispersions containing TLZ:PEG (1:5) and (1:10) compared to physical mixtures and pure TLZ. The effect of buffer on dissolution was studied. In general the dissolution of TLZ was less in phosphate buffered saline (PBS, pH 7.4) compared to Tris buffer. However, there was no significant difference in the extent of dissolution of TLZ from solid dispersions and physical mixture compared to pure TLZ. Solid dispersions prepared by solvent method showed faster dissolution rates compared to melt method. These results suggest that the rate of dissolution can be increased by improving the wetting property of tolazamide.     

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.