High Energy Ordered Mixture for Improving the Dissolution Rate of Sparingly Soluble Compounds

Abstract

Bioavailability of a sparingly soluble drug is often limited by the rate of dissolution of the drug substance. The drug in a micronized form is generally employed to maximize the bioavailability. However, the micronized drugs tend to agglomerates and do not always exhibit an improved dissolution rate. In this study, a simple processing using a high energy mill was demonstrated as an effective means to utilize the entire surface area available for drug release of the micronized drug. An experimental hydrophobic drug in a micronized form was milled with a carrier, hydrous lactose using Micropulverizer to achieve a uniform mixture so-called “high energy ordered mixture”. The high energy ordered mixture provided a contact surface area taking part in dissolution 4-fold greater than the micronized drug agglomerates. Therefore, the dissolution was significantly improved, irrespective of test parameters such as agitation and the presence of surfactant. This high energy ordered mixture provided the advantages over a simple ordered mixture for: (i) complete deaggregation of the micronized drug to fine primary particles, (ii) improving the efficiency of the carrier by increasing contact surface area, and (iii) enhancing the bonding effect between the drug and lactose particles due to free water molecules released from the crystal lattices of hydrous lactose during milling. This procedure could be applied to overcome dissolution problems of sparingly soluble drugs with cohesive nature.     

Influence of Magnesium Stearate on the Homogeneity of a Prednisone-Granule Ordered Mix

The use of ordered systems has been advocated in the formulation of microdose delivery systems to improve and maintain drug homogeneity during mixing. This study considered the effect of a lubricant such as magnesium stearate on the degree of homogeneity and stability of a preformed prednisone-granule ordered mix. Micronized prednisone was mixed with starch-lactose granules to produce an ordered mix of satisfactory homogeneity. Magnesium stearate in concentrations above and below the theoretical surface saturation of the granule caused negligible change in the degree of homogeneity. Sieve analysis of the mix and subsequent analysis of size fractions for prednisone allowed the prednisone distribution within the mix to be determined. Prednisone was found to be associated with the granules in all the mixes; the magnesium stearate did not compete for the surface adsorption sites and did not dislodge the drug from the granule surface, during mixing and mild demixing conditions. However, a decrease in surface adsorbed prednisone occurred in all mixes (with and without magnesium stearate) under more severe segregating conditions.

Recent research in drug homogeneity studies in microdose tablets has highlighted serious problems in dosage variation¹. Drugs are frequently micronized to improve their release from the solid dosage form. Micronization produces drug particles which are extremely cohesive and interactive. In practice, the adequate mixing of micronized powders with other excipients may be difficult to achieve since this cohesiveness produces aggregation of drug particles and interaction of the drug with the mixer surfaces. In recent years some research effort has been applied to using the interactive nature of drug particles to improve the homogeneity of mixes^2,3. Controlled adsorption of a micronized drug particle onto a carrier particle to produce an “ordered unit” has been shown to minimize segregation within the mix^4,5. Some of the factors affecting the degree of homogeneity of “ordered mixes” have been studied^6,7. However, little research has been conducted on the influence of other excipients on the homogeneity and stability of preformed ordered mixes. A cautionary note on the use of magnesium stearate in ordered mixtures indicated that the lubricant may displace salicylic acid from a sucrose carrier under conditions of segregation⁸. The purpose of this study, therefore, was to evaluate the influence of a third component such as magnesium stearate on the degree of homogeneity and stability of a preformed prednisone-starch lactose granule ordered system during a mixing process.     

Drug dispersion degree and drug dissolution rate in Hybrane S1200-based instant-release matricial particles prepared by hot melt extrusion

The objective of this study is to evaluate the dissolution of a poorly soluble drug (prednisolone) from different sized matricial particles (from <250 to >1500?µm) with two drug contents (10% or 20%) obtained by hot melt extrusion using the hyperbranched polyesteramide Hybrane S1200 (water-soluble and with a Tg of 45?°C) as the carrier. X-ray diffraction, differential scanning calorimetry and SEM studies permit us to conclude that in 10% prednisolone extrudate, the drug is mainly dispersed within the carrier, whereas in those containing 20% an important fraction of the drug remains in a crystalline state and is accumulated on the surface of the extrudates. On particles proceeding from 10% drug extrudate, the drug dissolution rate is very high and slightly dependant on particle size and in all cases, higher than the pure micronized drug. However, on particles proceeding from 20% prednisolone extrudate particle size have a major effect on drug dissolution rate, attributable to higher proportions of crystalline drug accumulated on the surface, hindering polymer dissolution. Thus, the reduction of the particle size after extrudate grinding creates new surfaces from inside, that leads to strong increments on prednisolone dissolution rate, and becomes higher than the pure micronized drug one when the particle size is <250?µm.     

Polydisperse powder mixtures: effect of particle size and shape on mixture stability

The effect of the shape and size of the components on the stability of mixtures was evaluated in binary mixtures of drug and carrier. Aspirin was used as model drug; spray-dried lactose and microcrystalline cellulose were used as carriers. The coefficient of variation (CV) of the drug in the mixture at various time intervals during mixing was used as a measure of homogeneity. The stability of mixtures was assessed under conditions that were conducive to segregation—in this case, prolonged mixing. The pattern of change in CV with time was analyzed in terms of convective, shear, and diffusive mixing stages. The variation resulting from a change in the shape of the carriers was smaller than that resulting from size differences. The segregation rate constant, calculated on the assumption of a first-order mixing process, was found to be larger in mixtures having components of different shape than in mixtures having components of similar shape. In mixtures of micronized drug and carrier, the pattern of change in the CV of drug with mixing time was attributed to the distribution of agglomerates of micronized drug during convective mixing, followed by shearing of agglomerates and, finally, the distribution of the primary particles during diffusive mixing. Mixtures of non-cohesive powders of similar size and shape behaved like random mixtures of non-interacting components.     

The Effect of Mixing Variables on the Dissolution Properties of Direct Compression Formulations of Furosemide

The particles of a number of poorly water soluble drugs, for instance furosemide, tend to agglonierate spontaneously and as a result decrease the drug's dissolution properties. This phenomena is undesirable when the drug is to be formulated in a direct compressible formulation. Interactive or ordered mixing with a filler usually rectifies this problem but the drug load is limited to a maxirnuni of ± 5% of the mixture. This is well below the formulation requirements of hrosemide (25 %) and below the maximum drug load which can be handled in dircct compression formulations (± 35 %). The effect of two types of mixers, the mixing time and drug load were investigated for a direct compression formulation of furosemide tablets. A Turbula and a V mixer, both with a volume of 720 ml, were used. The drug was formulated with Ludipress (a commercial direct compression filler, BASF, Germany) at two drug loadings of 20 and 25 %. Magnesium stearate (1 %) was added as a lubricant. A mixture was prepared for each experimental condition. After mixing the whole mixture (120 gram) was tabletted on a Korsch single punch machine producing ± 500 tablets. The crushing strength, mass and disintegration time of ten tablets and the dissolution of six tablets were measured. Dissolutions were donc according to the USP XXII - method 2¹ - in 0, 1 M HCI and a phosphate buffer with pH = 5.8. The intrinsic dissolution rates of some of the mixtures were also deterniined in the two dissolution media. The dissolution properties of the formulations were compared with the properties of Lasix®, a commercially available furoseniide product. which is not manufactured by dircct compression. The dissolution rates of the formulations mixed in the Turbula mixer were significantly higher than those mixed in the V miser. The area under the dissolution curves increased as a function of niixing time for both mixers. The best dissolution results were obtained for formulations with a 20 % drug load and mixed for 120 minutes in the Turbula miser. The dissolution curves for these formulations compared well with the curves for the commercial tablets. Intrinsic dissolution rates were also a hnction of niising time, which indicates that the increase in dissolution properties is probably a result of the deagglomeration of the agglomerated furosemide particles. The Turbula mixer, which can develop more shear force, breaks the agglomerates quicker and to a larger extend than the V mixer. It can be concluded that the type of mixer, mixing time and drug load control the dissolution properties of direct compression formulations of poorly water soluble drugs in which the drug particles form agglomerates.     

Polydisperse Powder Mixtures: Effect of Particle Size and Shape on Mixture Stability

ABSTRACT

The effect of the shape and size of the components on the stability of mixtures was evaluated in binary mixtures of drug and carrier. Aspirin was used as model drug; spray-dried lactose and microcrystalline cellulose were used as carriers. The coefficient of variation (CV) of the drug in the mixture at various time intervals during mixing was used as a measure of homogeneity. The stability of mixtures was assessed under conditions that were conducive to segregation—in this case, prolonged mixing. The pattern of change in CV with time was analyzed in terms of convective, shear, and diffusive mixing stages. The variation resulting from a change in the shape of the carriers was smaller than that resulting from size differences. The segregation rate constant, calculated on the assumption of a first-order mixing process, was found to be larger in mixtures having components of different shape than in mixtures having components of similar shape. In mixtures of micronized drug and carrier, the pattern of change in the CV of drug with mixing time was attributed to the distribution of agglomerates of micronized drug during convective mixing, followed by shearing of agglomerates and, finally, the distribution of the primary particles during diffusive mixing. Mixtures of non-cohesive powders of similar size and shape behaved like random mixtures of non-interacting components.     

The effect of particle morphology on the physical stability of pharmaceutical powder mixtures: the effect of surface roughness of the carrier on the stability of ordered mixtures

The effect of particle morphology of the components on the physical stability of ordered mixtures was determined for a model system comprised of a mixture of micronized aspirin and a monodisperse carrier. Spray-dried lactose, crystallized lactose, microcrystalline cellulose, and dextrate were used as carriers. The surface texture of the carriers was quantified in terms of the ratio of the perimeter of the particles to that of an idealized shape at a constant magnification. Mixtures containing highly textured carriers segregated to a lesser extent than those containing smoother textured carriers. This was postulated to be due to the presence of a higher concentration of surface asperities on the coarse carriers that can constitute potentially strong adhesion sites for the fine component because of their higher energy relative to adjacent areas on the surface. The effect of the addition of a ternary component, magnesium stearate, on the stability of the above mixtures was studied. The observed differences in the segregation response were attributed to electrostatic charge effects.     

The Effect of Particle Morphology on the Physical Stability of Pharmaceutical Powder Mixtures: The Effect of Surface Roughness of the Carrier on the Stability of Ordered Mixtures

The effect of particle morphology of the components on the physical stability of ordered mixtures was determined for a model system comprised of a mixture of micronized aspirin and a monodisperse carrier. Spray-dried lactose, crystallized lactose, microcrystalline cellulose, and dextrate were used as carriers. The surface texture of the carriers was quantified in terms of the ratio of the perimeter of the particles to that of an idealized shape at a constant magnification. Mixtures containing highly textured carriers segregated to a lesser extent than those containing smoother textured carriers. This was postulated to be due to the presence of a higher concentration of surface asperities on the coarse carriers that can constitute potentially strong adhesion sites for the fine component because of their higher energy relative to adjacent areas on the surface. The effect of the addition of a ternary component, magnesium stearate, on the stability of the above mixtures was studied. The observed differences in the segregation response were attributed to electrostatic charge effects.     

The Effect of Mixing Variables on the Dissolution Properties of Direct Compression Formulations of Furosemide

Abstract

The particles of a number of poorly water soluble drugs, for instance furosemide, tend to agglonierate spontaneously and as a result decrease the drug's dissolution properties. This phenomena is undesirable when the drug is to be formulated in a direct compressible formulation. Interactive or ordered mixing with a filler usually rectifies this problem but the drug load is limited to a maxirnuni of ± 5% of the mixture. This is well below the formulation requirements of hrosemide (25 %) and below the maximum drug load which can be handled in dircct compression formulations (± 35 %). The effect of two types of mixers, the mixing time and drug load were investigated for a direct compression formulation of furosemide tablets. A Turbula and a V mixer, both with a volume of 720 ml, were used. The drug was formulated with Ludipress (a commercial direct compression filler, BASF, Germany) at two drug loadings of 20 and 25 %. Magnesium stearate (1 %) was added as a lubricant. A mixture was prepared for each experimental condition. After mixing the whole mixture (120 gram) was tabletted on a Korsch single punch machine producing ± 500 tablets. The crushing strength, mass and disintegration time of ten tablets and the dissolution of six tablets were measured. Dissolutions were donc according to the USP XXII - method 2¹ - in 0, 1 M HCI and a phosphate buffer with pH = 5.8. The intrinsic dissolution rates of some of the mixtures were also deterniined in the two dissolution media. The dissolution properties of the formulations were compared with the properties of Lasix®, a commercially available furoseniide product. which is not manufactured by dircct compression. The dissolution rates of the formulations mixed in the Turbula mixer were significantly higher than those mixed in the V miser. The area under the dissolution curves increased as a function of niixing time for both mixers. The best dissolution results were obtained for formulations with a 20 % drug load and mixed for 120 minutes in the Turbula miser. The dissolution curves for these formulations compared well with the curves for the commercial tablets. Intrinsic dissolution rates were also a hnction of niising time, which indicates that the increase in dissolution properties is probably a result of the deagglomeration of the agglomerated furosemide particles. The Turbula mixer, which can develop more shear force, breaks the agglomerates quicker and to a larger extend than the V mixer. It can be concluded that the type of mixer, mixing time and drug load control the dissolution properties of direct compression formulations of poorly water soluble drugs in which the drug particles form agglomerates.     

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.     

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

Abstract

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.     

AGGREGATION DURING THE DISSOLUTION OF DIAZEPAM IN INTERACTIVE MIXTURES

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.     

The Influence of Various Dispersing Agents on the Dissolution Rate of Hydrochlorothiazide

The solvent and melt methods were employed to prepare solid dispersions with various water soluble carriers and sparingly soluble drug, hydrochlorothiazide. The carriers investigated included dextrose, sorbitol, tartaric acid and urea. Dispersion with urea was superior to other carriers in releasing the drug into solution. Dextrose - melt showed decomposition of the drug. Sorbitol drug physical mixture produced a faster rate of dissolution of the drug than the melt dispersions. The eutectic mixture of urea and drug cooled at room temperature (28°) produced a faster dissolution rate of the drug than the mixture cooled at -2°.     

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.     

Mechanistic investigation of mixing and segregation of ordered mixtures: experiments and numerical simulations

Pulmonary delivery of cohesive and micronized drugs through dry powder inhalers (DPIs) is traditionally achieved through the formation of ordered mixtures. In order to improve the mechanistic understanding of formation of ordered mixtures, the system consisting of micronized lactose (AZFL, representative of an active pharmaceutical ingredient) and a coarse particle carrier (LH100) is investigated as a function of different process and material variables in a high shear mixer (HSM) and in a low shear double cone (DCN) blender, using both experimental and numerical methods. Process insight is developed using a Discrete Element Method (DEM) based numerical model which could predict the formation of ordered mixtures in the two blenders and was verified against experimental determinations. Spatial and temporal evolution of granular flow are visualized and quantified in silico to reveal distinguishing features of both blenders to aid in rational selection of blenders and process parameters.     

Measurement of the Surface Area Changes During the Dissolution of Poorly Soluble Drugs using a Wide Angle Photosedimentometer

Using a Wide Angle Photosedimentometer, surface area changes during the dissolution of suspended particles of frusemide, glibenclamide and bendrofluazide have been measured. The method consisted of recording the change in optical density that occurs whilst the drugs are agitated in water in a 4cm square photosedimentometer cell. It was found that initially a high surface area was recorded which diminished exponentially with time and obeyed first order kinetics. From the surface area measurements, graphs of percentage drug dissolved against time were calculated and plotted and these profiles were found to correlate with similar plots of dissolution rate produced by analysing the amount dissolved spectrophotometrically. It was concluded that the surface area method offers an alternative technique for the measurement of the dissolution rate of poorly water soluble drugs, particularly when no adequate method exists for analysing the dissolved fraction.     

The Influence of Various Dispersing Agents on the Dissolution Rate of Hydrochlorothiazide

Abstract

The solvent and melt methods were employed to prepare solid dispersions with various water soluble carriers and sparingly soluble drug, hydrochlorothiazide. The carriers investigated included dextrose, sorbitol, tartaric acid and urea. Dispersion with urea was superior to other carriers in releasing the drug into solution. Dextrose - melt showed decomposition of the drug. Sorbitol drug physical mixture produced a faster rate of dissolution of the drug than the melt dispersions. The eutectic mixture of urea and drug cooled at room temperature (28°) produced a faster dissolution rate of the drug than the mixture cooled at -2°.     

Measurement of the Surface Area Changes During the Dissolution of Poorly Soluble Drugs using a Wide Angle Photosedimentometer

Abstract

Using a Wide Angle Photosedimentometer, surface area changes during the dissolution of suspended particles of frusemide, glibenclamide and bendrofluazide have been measured. The method consisted of recording the change in optical density that occurs whilst the drugs are agitated in water in a 4cm square photosedimentometer cell. It was found that initially a high surface area was recorded which diminished exponentially with time and obeyed first order kinetics. From the surface area measurements, graphs of percentage drug dissolved against time were calculated and plotted and these profiles were found to correlate with similar plots of dissolution rate produced by analysing the amount dissolved spectrophotometrically. It was concluded that the surface area method offers an alternative technique for the measurement of the dissolution rate of poorly water soluble drugs, particularly when no adequate method exists for analysing the dissolved fraction.     

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.     

Crystal engineering of lactose using electrospray technology: carrier for pulmonary drug delivery

Context: Dry powder inhalers (DPIs) consisting of a powder mixture containing coarse carrier particles (generally lactose) and micronized drug particles are used for lung drug delivery. The effective drug delivery to the lungs depends on size and shape of carrier particles. Thus, various methods have been proposed for engineering lactose particles to enhance drug delivery to lungs.

Objective: The objective of current work was to assess suitability of electrospray technology toward crystal engineering of lactose. Further, utility of the prepared lactose particles as a carrier in DPI was evaluated.

Materials and methods: Saturated lactose solutions were electrosprayed to obtain electrosprayed lactose (EL) particles. The polymorphic form of EL was determined using Fourier transform infrared spectroscopy, powder X-ray diffractometry, and differential scanning calorimetry. In addition, morphological, surface textural, and flow properties of EL were determined using scanning electron microscopy and Carr’s index, respectively. The aerosolization properties of EL were determined using twin-stage impinger and compared with commercial lactose particles [Respitose^® (SV003, Goch, Germany)] used in DPI formulations.

Results and discussion: EL was found to contain both isomers (α and β) of lactose having flow properties comparable to Respitose^® (SV003). In addition, the aerosolization properties of EL were found to be significantly improved when compared to Respitose^® (SV003) which could be attributed to morphological (high elongation ratio) and surface characteristic (smooth surface) alterations induced by electrospray technology.

Conclusion: Electrospray technology can serve as an alternative technique for continuous manufacturing of engineered lactose particles which can be used as a carrier in DPI formulations.