Effect of amorphous content on dissolution characteristics of rifampicin

Rifampicin, one of the main first line anti-TB drugs, shows variable bioavailability in different marketed preparations and reasons cited include physiological, degradation, manufacturing/ processing, solid state, and bioavailability assessment procedure. Although the amorphous form of a drug is expected to exhibit higher solubility, the amorphous rifampicin has been reported to have a solubility disadvantage as compared to crystalline form II, which is used in marketed preparations. Amorphous form was generated and characterized by solid-state characterization techniques. Physical powder mixtures of form II with varying amounts of amorphous form were prepared, which were then subjected to solid-state characterization techniques and further evaluated for their dissolution behavior. Differential scanning calorimetry (DSC) scans show that area enclosed by integral of melting endotherm can be used for quantification of crystalline component, which can then be used to estimate amorphous content. No definite trend was evident in powder dissolution of mixtures that could implicate solubility difference of amorphous form. Intrinsic dissolution rate (IDR) results indicate that amorphous content has no effect on dissolution profiles of crystalline rifampicin.     

Effect of Amorphous Content on Dissolution Characteristics of Rifampicin

Rifampicin, one of the main first line anti-TB drugs, shows variable bioavailability in different marketed preparations and reasons cited include physiological, degradation, manufacturing/ processing, solid state, and bioavailability assessment procedure. Although the amorphous form of a drug is expected to exhibit higher solubility, the amorphous rifampicin has been reported to have a solubility disadvantage as compared to crystalline form II, which is used in marketed preparations. Amorphous form was generated and characterized by solid-state characterization techniques. Physical powder mixtures of form II with varying amounts of amorphous form were prepared, which were then subjected to solid-state characterization techniques and further evaluated for their dissolution behavior. Differential scanning calorimetry (DSC) scans show that area enclosed by integral of melting endotherm can be used for quantification of crystalline component, which can then be used to estimate amorphous content. No definite trend was evident in powder dissolution of mixtures that could implicate solubility difference of amorphous form. Intrinsic dissolution rate (IDR) results indicate that amorphous content has no effect on dissolution profiles of crystalline rifampicin.     

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.     

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.     

Effect of Agitation Intensity on the Dissolution Rate of Indomethacin and Indomethacin-Citric Acid Compressed Discs

Abstract

The dissolution rates of indomethacin (IMC) and indomethacin-citric acid (monohydrate) 1:1 mixtures under various hydrodynamic conditions were determined in a phosphate buffered medium Dissolution profiles of the γ form of IMC were nonlinear the rates decreasing with time The dissolution rates increased with increasing stirring speed In contrast α-IMC gave linear dissolution profiles the rates being higher and more sensitive to agitation intensity than those obtained using the γ-form. The slope of a log dissolution rate versus log stirring speed plot had a value of 0.598 for γ-IMC and 0.171 for γ-IMC Indomethacin dissolution rates from the mixed discs were 5-10 times lower than those of pure γ-IMCin the stirring speed range 180-60 rpm respectively The dissolution profiles of IMC showed positive curvature at low stirring speed while at high stirring speed the dissolution profiles became linear The slope of the log dissolution rate versus log stirring speed plot was nonlinear and ranged from >1 at low stirring speed to <0.5 at high stirring speed.     

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.     

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.     

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.     

Solid State Interaction of Raloxifene HCl with Different Hydrophilic Carriers During Co-grinding and its Effect on Dissolution Rate

This study investigated the effects of different classes of hydrophilic carriers (poly vinyl pyrrolidones [PVPs] [Plasdone K-25 and Plasdone S-630], cellulosic polymers [hydroxypropyl methyl cellulose and hydroxy propyl cellulose], and Sodium Alginate) on the solid state and dissolution rate of Raloxifene hydrochloride (R-HCl). Solid state characterizations of co-ground mixtures and physical mixtures in 1:1 and 1:2 ratios of drug to polymer were performed by employing laser diffractometer for particle size and differential scanning calorimetry (DSC) for solid state interactions. The results of particle size studies showed that only co-grinding with PVPs was more effective in the reduction of particle size than the milling of drug alone. DSC study indicated that the crystalline nature of the drug was reduced after co-grinding with PVPs when compared with their corresponding physical mixtures. The hydrophilic carriers other than PVPs did not reduce the crystalline nature of the drug significantly. X-ray diffraction and scanning electron microscopy were carried out for selected batches to confirm DSC results. Significant enhancement in dissolution rate and extent was observed with co-ground mixtures of drug and PVPs. Plasdone S-630 was found to be a better carrier for R-HCl in terms of achieving improvement in dissolution. In vitro dissolution data can be described by Hixson–Crowell model, indicating the drug release mechanism predominated by erosion.     

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.     

Evaluating spray gelation and spray freeze drying as the granulation method to prepare oral tablets of amorphous drug nanoplex

Amorphous drug nanoplex represents one of the most promising solubility enhancement strategies of poorly-soluble drugs. Solubility enhancement capability of nanoplex hitherto has been demonstrated for nanoplex suspension and lyophilized/spray-dried nanoplex, but not for its oral tablets. Using ciprofloxacin as the model poorly-soluble drug, we investigated spray gelation (SG) of alginate and spray freeze drying (SFD) with cryoprotective mannitol, as the nanoplex’s granulation methods. Both granules were evaluated in terms of their morphology, physical form, flowability, drug content, preparation yield, dissolution profile, drug solubility enhancement, and storage stability. Subsequently, tablets of the granules were prepared and characterized in terms of their drug content uniformity, weight variation, friability, hardness, dissolution profile, and solubility enhancement. The results showed that nanoplex in SG granules was embedded in dense amorphous alginate matrix, while nanoplex in SFD granules was dispersed in porous crystalline mannitol particles. Despite their distinct morphology, physical form, and dissolution profile, the two granules exhibited similar drug solubility enhancements. Both granules were readily compacted into tablets with minimal changes in their dissolution and solubility enhancement after tableting. The present work demonstrated SG and SFD as viable granulation methods of nanoplex, with SG granules exhibiting superior flowability, stability, but lower yield.     

Effect of melt sonocrystallization on pharmacotechnical properties of paracetamol,indomethacin and mefenamic acid characterized by dynamic laser scattering and its impact on solubility

The purpose of the research was to employ a novel particle engineering technique-melt sonocrystallization (MSC) for some nonsteroidal anti-inflammatory drugs for development of more soluble forms of the drugs without the use of excipients. The original forms of Paracetamol (OFPCM), Indomethacin (OFIMC) and Mefenamic acid (OFMA) were subjected to MSC to improve physicochemical properties. MSC forms of PCM, IMC and MA were subjected to dynamic laser scattering for particle size analysis to quantize mean particle size, specific surface area, interquartile coefficient of skewness, kurtosis and span. Rheological and solubility analysis, X-ray powder diffraction and scanning electron microscopy were conducted for validating the effect of MSC on powder particles. On melt sonocrystallized form of drug powders exhibited improved micromeritic properties, the mean particle size was reduced while the specific surface area increased effectively. Frequency distribution curves showed reduction in asymmetry and skewness that was confirmed by interquartile coefficient of skewness values. Equilibrium solubility of MSC form of PCM, IMC and MA was higher than the original forms. Similarly the intrinsic dissolution rate was approximately 1.5 times higher in comparison to original form of drugs. X-ray powder diffraction shows decreased relative intensities of peaks of MSC forms due to reduction in the crystallinity that was confirmed by visualization of MSC particles by scanning electron microscopy. Conclusively, MSC is a promising cost-effective technique that may afford powder with improved flow and formulative properties as well as improved solubility and dissolution.     

Solid-state amorphization of rebamipide and investigation on solubility and stability of the amorphous form

Solid-state amorphization of crystalline rebamipide (RBM) was realized by ball milling and spray drying. The amorphous content of samples milled for various time was quantified using X-ray powder diffraction. Crystalline RBM and three amorphous RBM obtained by milling and spray drying were characterized by morphological analysis, X-ray diffraction, thermal analysis and vibrational spectroscopy. The crystal structure of RBM was first determined by single-crystal X-ray diffraction. In addition, the solubility and dissolution rate of the RBM samples were investigated in different media. Results indicated that the solubility and the dissolution rates of spray-dried RBM-PVP in different media were highly improved compared with crystalline RBM. The physical stabilities of the three amorphous RBM were systematically investigated, and the stability orders under different storage temperatures and levels of relative humidity (RH) were both as follows: spray dried RBM?相似文献   

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.     

The development of a modified dissolution method suitable for investigating powder mixtures

A novel dissolution method was developed, suitable for powder mixtures, based on the USP basket apparatus. The baskets were modified such that the powder mixtures were retained within the baskets and not dispersed, a potential difficulty that may arise when using conventional USP basket and paddle apparatus. The advantages of this method were that the components of the mixtures were maintained in close proximity, maximizing any drug: excipient interaction and leading to more linear dissolution profiles. Two weakly acidic model drugs, ibuprofen and acetaminophen, and a selection of pharmaceutical excipients, including potential dissolution-enhancing alkalizing agents, were chosen for investigation. Dissolution profiles were obtained for simple physical mixtures. The f1 fit factor values, calculated using pure drug as the reference material, demonstrated a trend in line with expectations, with several dissolution enhancers apparent for both drugs. Also, the dissolution rates were linear over substantial parts of the profiles. For both drugs, a rank order comparison between the f1 fit factor and calculated dissolution rate, obtained from the linear section of the dissolution profile, demonstrated a correlation using a significance level of P = 0.05. The method was proven to be suitable for discriminating between the effects of excipients on the dissolution of the model drugs. The method design produced dissolution profiles where the dissolution rate was linear for a substantial time, allowing determination of the dissolution rate without mathematical transformation of the data. This method may be suitable as a preliminary excipient-screening tool in the drug formulation development process.     

Isothermal and Dynamic Microcalorimetry for Quantifying the Crystallization of an Amorphous Drug during Interactive Powder Mixing

This study reports the crystallization of amorphous nifedipine during an interactive mixing process quantified by using isothermal and dynamic microcalorimetry. Interactive mixtures of amorphous nifedipine and uniform glass beads were prepared by mixing in a Turbula® mixer. The difference in the extent of crystallization of amorphous nifedipine during mixing was characterized by the time it took for the crystallization of a known amount of amorphous nifedipine in isothermal calorimetry and the change in the height of the crystallization peak at 65°C in dynamic calorimetry. It was found that both isothermal and dynamic microcalorimetry are useful techniques for quantifying the physical transition of amorphous nifedipine during interactive mixing. The rate and extent of crystallization of amorphous nifedipine depended on both mixing time and speed, but mixing time played a more dominant role because the transformation of amorphous to crystalline nifedipine was greater after 3180 revolutions (9.7%) than after 405 revolutions (0.9%) at 27 rpm. The same trend was observed at 109 rpm, but the percentage of crystalline nifedipine after 3180 revolutions was only 5.2%. This meant that an increase in mixing time rather than speed increased the rate of amorphous to crystalline transformation. The greatest cause for crystal transformation during interactive mixing was the presence of crystal seeds of the thermodynamically stable nifedipine Modification I because the amount of amorphous to crystalline transformation increased from 2.6% for a completely amorphous mixture to 6.6% for a 92:8 mixture of amorphous and crystalline nifedipine when mixed for 30 minutes at 106 rpm.     

Isothermal and Dynamic Microcalorimetry for Quantifying the Crystallization of an Amorphous Drug during Interactive Powder Mixing

ABSTRACT

This study reports the crystallization of amorphous nifedipine during an interactive mixing process quantified by using isothermal and dynamic microcalorimetry. Interactive mixtures of amorphous nifedipine and uniform glass beads were prepared by mixing in a Turbula® mixer. The difference in the extent of crystallization of amorphous nifedipine during mixing was characterized by the time it took for the crystallization of a known amount of amorphous nifedipine in isothermal calorimetry and the change in the height of the crystallization peak at 65°C in dynamic calorimetry. It was found that both isothermal and dynamic microcalorimetry are useful techniques for quantifying the physical transition of amorphous nifedipine during interactive mixing. The rate and extent of crystallization of amorphous nifedipine depended on both mixing time and speed, but mixing time played a more dominant role because the transformation of amorphous to crystalline nifedipine was greater after 3180 revolutions (9.7%) than after 405 revolutions (0.9%) at 27 rpm. The same trend was observed at 109 rpm, but the percentage of crystalline nifedipine after 3180 revolutions was only 5.2%. This meant that an increase in mixing time rather than speed increased the rate of amorphous to crystalline transformation. The greatest cause for crystal transformation during interactive mixing was the presence of crystal seeds of the thermodynamically stable nifedipine Modification I because the amount of amorphous to crystalline transformation increased from 2.6% for a completely amorphous mixture to 6.6% for a 92:8 mixture of amorphous and crystalline nifedipine when mixed for 30 minutes at 106 rpm.     

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.     

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.     

Molecular dynamics investigation of mechanical mixing in mechanical alloying

Molecular dynamic simulation is exploited to obtain a deep insight of atomic scale mixing and amorphization mechanisms happening during mechanical mixing. Impact–relaxation cycles are performed to simulate the mechanical alloying process. The results obtained by structural analysis shows that the final structure obtained through simulation of mechanical alloying is in an amorphous state. This analysis reveals that amorphization occurs concurrently with the attainment of a perfectly mixed alloy. The results indicate diffusion and deformation are two important mechanisms for mixing during mechanical alloying. The rate of diffusion is controlled by the temperature and by the density of defects in the structure. Deformation enhances mixing directly by sliding atomic layers on each other and increases the number of defects in the structure. The results agree with mechanical alloying experiments described in the literature.