The preparation of agglomerates containing solid dispersions of diazepam by melt agglomeration in a high shear mixer

The aim of this study was to prepare by melt agglomeration agglomerates containing solid dispersions of diazepam as poorly water-soluble model drug in order to evaluate the possibility of improving the dissolution rate. Lactose monohydrate was melt agglomerated with polyethylene glycol (PEG) 3000 or Gelucire 50/13 (mixture of glycerides and PEG esters of fatty acids) as meltable binders in a high shear mixer. The binders were added either as a mixture of melted binder and diazepam by a pump-on procedure or by a melt-in procedure of solid binder particles. Different drug concentrations, maximum manufacturing temperatures, and cooling rates were investigated. It was found to be possible to increase the dissolution rate of diazepam by melt agglomeration. A higher dissolution rate was obtained with a lower drug concentration. Admixing the binders by the melt-in procedure resulted in similar dissolution rates as the pump-on procedure. The different maximum manufacturing temperatures and cooling rates were found to have complex effects on the dissolution rate for formulations containing PEG 3000, whereas only minor effects of the cooling procedure were found with Gelucire 50/13. Gelucire 50/13 resulted in faster dissolution rates compared to PEG 3000.     

Effect of a melt agglomeration process on agglomerates containing solid dispersions

The purpose was to produce solid dispersions of a poorly water-soluble drug, Lu-X, by melt agglomeration in a laboratory scale rotary processor. The effect of binder type and method of manufacturing on the dissolution profile of Lu-X was investigated. Lactose monohydrate and Lu-X were melt agglomerated with Rylo MG12, Gelucire 50/13, PEG 3000, or poloxamer 188. Either a mixture of binder, drug, and excipient was heated to a temperature above the melting point of the binder (melt-in procedure) or a dispersion of drug in molten binder was sprayed on the heated excipient (spray-on procedure). The agglomerates were characterized by DSC, XRPD, SEM, and EDX-SEM. The study showed that the agglomerates containing solid dispersions had improved dissolution rates compared to physical mixtures and pure drug. The melt-in procedure gave a higher dissolution rate than the spray-on procedure with PEG 3000, poloxamer 188, and Gelucire 50/13, whereas the opposite was found with Rylo MG12. This was explained by differences in mechanisms of agglomerate formation and growth, which were dominated by immersion with PEG 3000, poloxamer 188, and Gelucire 50/13, and by distribution and coalescence with Rylo MG12. The spray-on procedure resulted in a higher content of Lu-X in the core of the agglomerates when immersion was the dominating mechanism, and in a higher content in the agglomerate surface when distribution was dominating. The melt-in procedure resulted generally in a homogeneous distribution of Lu-X in the agglomerates. The compounds in the agglomerates were found primarily to be crystalline, and the dissolution profiles were unchanged after 12 weeks storage at 25 degrees C at 50% RH.     

Melt agglomeration with polyethylene glycol beads at a low impeller speed in a high shear mixer.

This study was performed in order to evaluate the possibility of obtaining spherical agglomerates with a high content of meltable binder by a melt agglomeration process in a high shear mixer. Lactose monohydrate was melt agglomerated with polyethylene glycol (PEG) 1500 or 6000 in a 10-l high shear mixer at an impeller speed of 400 rpm. The PEG 1500 was used as a size fraction of beads, and the PEG 6000 as a fine powder, a powder, unfractionated beads, and size fractions of beads. It was found to be possible to incorporate a high amount of PEG (28% m/m of the amount of lactose), because the rather low impeller speed applied in the present experiments caused less densification of the agglomerates. The fine powder of the PEG 6000 caused a complete adhesion of the mass to the bowl shortly after melting. A rapid agglomerate growth by coalescence was found to be the dominant growth mechanism when agglomeration was performed with the PEG 6000 powder. The PEG beads resulted in a slow and more controllable agglomerate growth, because the growth occurred primarily by an immersion of the lactose particles in the surface of the molten binder droplets. The initial shape of the agglomerates produced with the PEG beads was similar to the spherical shape of the beads. This shape could not be maintained during the process due to a breakage of the agglomerates caused by a hollow structure of the PEG beads.     

Effects of droplet size and type of binder on the agglomerate growth mechanisms by melt agglomeration in a fluidised bed.

This study was performed in order to evaluate the effects of binder droplet size and type of binder on the agglomerate growth mechanisms by melt agglomeration in a fluidised bed granulator. Lactose monohydrate was agglomerated with melted polyethylene glycol (PEG) 3000 or Gelucire 50/13 (esters of polyethylene glycol and glycerol), which was atomised at different nozzle air flow rates giving rise to median droplet sizes of 40, 60, and 80 microm. Different product temperatures were investigated, below the melting range, in the middle of the melting range, and above the melting range for each binder. The agglomerates were found to be formed by initial nucleation of lactose particles immersed in the melted binder droplets. Agglomerate growth occurred by coalescence between nuclei followed by coalescence between agglomerates. Complex effects of binder droplet size and type of binder were seen at low product temperatures. Low product temperatures resulted in smaller agglomerate sizes, because the agglomerate growth was counteracted by very high binder viscosity or solidification of the binder. At higher product temperatures, neither the binder droplet size nor the type of binder had a clear effect on the final agglomerate size.     

Effects of physical properties of powder particles on binder liquid requirement and agglomerate growth mechanisms in a high shear mixer.

A study was performed in order to elucidate the effects of the physical properties of small powder particles on binder liquid requirement and agglomerate growth mechanisms. Three grades of calcium carbonate having different particle size distribution, surface area, and particle shape but approximately the same median particle size (4-5 microm), were melt agglomerated with polyethylene glycol (PEG) 3000 or 20,000 in an 8-l high shear mixer at three impeller speeds. The binder liquid requirement was found to be very dependent on the packing properties of the powder, a denser packing resulting in a lower binder liquid requirement. The densification of the agglomerates in the high shear mixer could be approximately predicted by compressing a powder sample in a compaction simulator. With the PEG having the highest viscosity (PEG 20,000), the agglomerate formation and growth occurred primarily by the immersion mechanism, whereas PEG 3000 gave rise to agglomerate growth by coalescence. Powder particles with a rounded shape and a narrow size distribution resulted in breakage of agglomerates with PEG 3000, whereas no breakage was seen with PEG 20,000. Powder particles having an irregular shape and surface structure could be agglomerated with PEG 20,000, whereas agglomerate growth became uncontrollable with PEG 3000. When PEG 20,000 was added as a powder instead of flakes, the resultant agglomerates became rounder and the size distribution narrower.     

Physicochemical characterization of solid dispersions of the antiviral agent UC-781 with polyethylene glycol 6000 and Gelucire 44/14

The purpose of this study was to prepare and characterize solid dispersions of the antiviral thiocarboxanilide UC-781 with PEG 6000 and Gelucire 44/14 with the intention of improving its dissolution properties. The solid dispersions were prepared by the fusion method. Evaluation of the properties of the dispersions was performed using dissolution studies, differential scanning calorimetry, Fourier-transform infrared spectroscopy and X-ray powder diffraction. To investigate the possible formation of solid solutions of the drug in the carriers, the lattice spacings [d] of PEG 6000 and Gelucire 44/14 were determined in different concentrations of UC-781. The results obtained showed that the rate of dissolution of UC-781 was considerably improved when formulated in solid dispersions with PEG 6000 and Gelucire 44/14 as compared to pure UC-781. From the phase diagrams of PEG 6000 and Gelucire 44/14 it could be noted that up to approximately 25% w/w of the drug was dissolved in the liquid phase in the case of PEG 6000 and Gelucire 44/14. The data from the X-ray diffraction showed that the drug was still detectable in the solid state below a concentration of 5% w/w in the presence of PEG 6000 and Gelucire 44/14, while no significant changes in the lattice spacings of PEG 6000 or Gelucire 44/14 were observed. Therefore, the possibility of UC-781 to form solid solutions with the carriers under investigation was ruled out. The results from infrared spectroscopy together with those from X-ray diffraction and differential scanning calorimetry showed the absence of well-defined drug–polymer interactions.     

Influence of binder properties, method of addition, powder type and operating conditions on fluid-bed melt granulation and resulting tablet properties.

The aim of the study was to investigate melt granulation in a laboratory scale fluid-bed granulator with respect to granule growth, granule properties and resulting tablet properties. The parameters investigated were method of addition of PEG (spray-on or addition as flakes), binder concentration, PEG type (3000, 4000 and 6000, sprayed-on), size (PEG 4000, added as three different sized flakes), powder type (two different sized lactose types and corn starch) and operating conditions (volume air flow and heating temperature). Addition of binder as flakes led to layering as a growth mechanism when the size of the flakes was high. Coalescence occurred when the size was low. Coalescence also occurred when spraying was the method of addition. Due to the greater viscosity of the PEG 6000 melt it produced bigger granules than 3000 or 4000. The influence of volume air flow was moderate and the influence of heating temperature in the range of 70-90 degrees C was very low with both methods of addition. The disintegration time of tablets from granules where PEG was added as flakes was shorter than from granules where PEG was sprayed-on. The latter method of binder addition led to tablets which did not disintegrate but eroded. This was apparently caused by formation of a binder matrix, which could not be destroyed by the disintegrant.     

Diclofenac salts, II. Solid dispersions in PEG6000 and Gelucire 50/13.

A number of systems were prepared at five compositions (5, 10, 20, 30 and 40% w/w) of diclofenac/N-(2-hydroxyethyl) pyrrolidine salt and acidic diclofenac in PEG6000 and Gelucire 50/13, as physical mixtures and as solid dispersions. Powder X-ray diffractograms for the systems examined show shifted and normal peaks, suggesting that the drug is present inside the samples in different physical states. Differential scanning calorimetry does not offer important information, since drug solubility into the carriers increases with temperature and thermograms show only the melting point peak of the carriers. Hot-stage microscopy examination explains that, in high concentration samples, the drug is present either dissolved into the carriers, or precipitated as microcrystals, or undissolved crystals of larger size. Gelucire 50/13 allows the formation of larger crystals than PEG, using both the chemical forms of the drug. The release percentage of the drug from PEG6000/acidic diclofenac reaches 50% after few minutes in the most favourable case and appears to be dependent on the composition of the samples: the more diclofenac is present as dissolved in the pre-treated samples, the higher is the release. The optimum composition was found in the range of 5-10% w/w.     

Melt pelletization in a high shear mixer. V. Effects of apparatus variables

Effects of two different sets of impeller blades on melt pelletization of lactose with polyethylene glycol (PEG) 3000 were investigated in an 8 litre high shear mixer. Results obtained in the 8 litre mixer were compared with previous results from a 50 litre high shear mixer of the same type. In the 8 litre mixer curved impeller blades were found to give rise to a high power input and smooth pellets of a spherical shape, whereas plane impeller blades caused a lower power input and irregular agglomerates. Agglomerate growth was found to be different in mixers of different scale. This difference was primarily ascribed to differences in movement of the mass, power input and product temperature.     

Aerosolisation of beclomethasone dipropionate using spray dried lactose/polyethylene glycol carriers.

The aim of this study was to characterize the physical properties of spray dried lactose in the presence of different polyethylene glycols (PEG 400, PEG 3000 and PEG 6000) and to evaluate their performance as carriers for dry powder inhaler (DPI) formulations. The efficiency of spray dried lactose/PEG carriers in aerosolisation of beclomethasone dipropionate (BD), a model hydrophobic drug, was compared to Pharmatose 325 M (L325), spray dried lactose alone (SDL), and also a sieved (< 38 microm) fraction of alpha-lactose monohydrate (SL). In vitro deposition analysis was performed using a twin stage liquid impinger at a flow rate of 60 l/min through a Spinhaler. The deposition profiles of the drug from binary formulations composed of BD and spray dried lactose/PEG carriers were also compared to ternary formulations containing large and fine lactose carriers. Differential scanning calorimetry and X-ray diffraction data showed the presence of alpha-anhydrous lactose in spray dried lactose/PEG crystalline powders. Spray drying of lactose in the presence of PEG 400 resulted in the production of a powder (SDL-PEG400) with lower alpha-lactose monohydrate content, and also smaller particle size distribution than those obtained in the presence of PEG 3000 (SDL-PEG3000) or PEG 6000 (SDL-PEG6000). All formulations showed different deposition profiles, except those containing SDL-PEG3000 or SDL-PEG6000 which exhibited similar data. The fine particle fraction of aerosolised BD varied from 6.26 +/- 1.07 (for L325) to 25.87 +/- 5.33 (for SDL-PEG3000). All deposition profiles of BD aerosolised from SDL-PEG3000 were significantly higher (P < 0.01) than those produced by binary and ternary formulations containing L325, a coarse lactose commercially available for DPI formulations. The differences observed in deposition data for various carriers were interpreted according to their physical properties. It was concluded that particle size distribution, morphology and specific surface texture of SDL-PEG3000 and SDL-PEG6000 were important factors influencing their efficiency as small carriers for DPI formulations.     

The effect of droplet size and powder particle size on the mechanisms of nucleation and growth in fluid bed melt agglomeration

This study was performed in order to evaluate the effects of binder droplet size and powder particle size on agglomerate formation and growth in fluid bed spray agglomeration using a meltable binder. Three different lactose grades, 100, 125 or 350 mesh, were agglomerated using polyethylene glycol (PEG) 3000 at two different concentrations, 11.5 or 22% (volume/mass), and three spray droplet sizes, 30, 60 or 90 microm were applied. The ratio of droplet size/particle size was found to determine whether the mechanism of nucleation was distribution or immersion. Distribution was promoted by a low ratio, whereas immersion was promoted by a high ratio. Distribution as nucleation mechanism led to a more open agglomerate structure and immersion to a denser structure. When the nucleation phase was terminated, coalescence between rewetted nuclei or agglomerates was the growth mechanism with both preceding mechanisms of nucleation. A larger particle size of the lactose led to larger agglomerates. The difference in the effect on growth between the 30 and 60 microm droplets was generally low. The 90 microm droplets at 22% binder concentration offered a potential for uncontrollable growth giving rise to markedly larger agglomerates and a lower reproducibility than 30 and 60 microm droplets.     

Moisture Uptake of Polyoxyethylene Glycol Glycerides Used as Matrices for Drug Delivery: Kinetic Modelling and Practical Implications

Purpose

Gelucire 50/13, a polyoxyethylene glycol glyceride mixture, has been widely used in drug delivery, but its moisture uptake behaviour is still poorly understood. In this study, the effects of relative humidity, temperature, and drug incorporation on the moisture uptake of Gelucire are reported in relation to their practical implications for preparation of solid dispersions using this material.

Methods

DVS combined with kinetics modelling was used as the main experimental method to study the moisture uptake behaviour of Gelucire. Thermal and microscopic methods were employed to investigate the effect of moisture uptake on the physical properties of the material and drug loaded solid dispersions.

Results

The moisture uptake by Gelucire 50/13 is temperature and relative humidity dependent. At low temperatures and low relative humidities, moisture sorption follows a GAB model. The model fitting indicated that at high relative humidities the sorption is a complex process, potentially involving PEG being dissolved and the PEG solution acting as solvent to dissolve other components.

Conclusion

Careful control of the storage and processing environmental conditions are required when using Gelucire 50/13. The incorporation of model drugs not only influences the moisture uptake capacity of Gelucire 50/13 but also the solidification behaviour.     

Physical stability of solid dispersions of the antiviral agent UC-781 with PEG 6000, Gelucire 44/14 and PVP K30

This paper describes the physical stability of solid dispersions of UC-781 with PEG 6000, Gelucire 44/14 and PVP K30 prepared by the solvent and melting methods. The concentration of the drug in the solid dispersions ranged from 5 to 80% w/w. The solid dispersions were stored at 4-8 and 25 degrees C (25% RH), then their physicochemical properties were analysed by differential scanning calorimetry (DSC), X-ray powder diffraction and dissolution studies as a function of storage time. The DSC curves of solid dispersions of UC-781 with PVP K30 did not show any melting peaks corresponding to UC-781 after storage, indicating no recrystallization of the drug. The DSC data obtained from PEG 6000 and Gelucire 44/14 showed some variations in melting peak temperatures and enthalpy of fusion of the carriers. It was shown that the enthalpy of fusion of PEG 6000 in the dispersions increased after storage; it was more pronounced for samples stored at 25 degrees C compared to those at 4-8 degrees C indicating the reorganization of the crystalline domains of the polymer. Similarly, the enthalpy of fusion of Gelucire 44/14 in the solid dispersions increased as a function of time. Dissolution of UC-781 from all solid dispersions decreased as a function of storage time. While these observations concurred with the DSC data for all solid dispersions, they were not reflected by X-ray powder diffraction data. It was concluded that it is the change of the physical state of the carriers and not that of the drug, which is responsible for the decreased dissolution properties of the solid dispersions investigated.     

Melt pelletization with polyethylene glycol in a rotary processor

The purpose of this study was to investigate the effect of the airflow, the binder concentration, the massing time, the friction plate rotation speed, and the surface structure of the friction plate on melt pelletization in a laboratory scale rotary processor. Lactose monohydrate was melt agglomerated with polyethylene glycol (PEG) 3000 as meltable binder. The study was performed as a full factorial design. An increase in agglomerate size was found when the binder concentration, the massing time, or the friction plate rotation speed was increased. The agglomerate size was also increased when increasing the shearing forces by using a friction plate with a different surface structure. The size distribution of the agglomerates was significantly narrowed when the binder concentration or the shearing forces caused by the friction plate were increased. An increase in the adhesion of material to the friction plate was found when the shearing forces of the friction plate were increased either by the rotation speed or by the surface structure. Generally, the rotary processor was found to be a suitable alternative to melt pelletization in a high shear mixer.     

Formulation of sustained-release verapamil HCl and diltiazem HCl semisolid matrix capsules

Semisolid matrix capsule formulations of verapamil HCl and diltiazem HCl prepared by hot-melt capsule filling are an especially appealing and simple way to make sustained-release formulations. Semisolid matrices of Gelucire 50/13 and stearic acid combination eroded and disintegrated at various rates, depending on the combination of waxes, and drug release rates were dependent on storage time (2.5 years) and temperature. Semisolid matrices of combinations of only Gelucire 50/13 and cetyl alcohol eroded at a rate much less than combinations of Gelucire 50/13 and stearic acid. The drug release mechanism from Gelucire 50/13: stearic acid matrices involved diffusion and erosion, whereas Gelucire 50/13 and cetyl alcohol matrices exhibited a diffusion mechanism only. A combination of Gelucire 50/13 with cetyl alcohol is more effective than stearic acid in appropriately extending verapamil HCl release from semisolid matrix capsules. The semisolid matrix formulations studied are sensitive to dissolution stirring speeds.     

Optimization of melt pelletization in a high shear mixer

The effects of process conditions and binder content on the process yield and pellet characteristics of two formulations prepared by melt pelletization in a laboratory-type high shear mixer were investigated. The formulations were prepared using Gelucire^® 50/13 and Lutrol^® F68 as meltable binders. The factors under investigation were impeller speed, mixing time, mixer load, binder concentration, and their reciprocal interactions. Analysis of variance (ANOVA) was used in order to study the significance of above mentioned process variables on the useful yield. Twenty-seven experiments were required for the response surface methodology based on Box–Behnken experimental design (24 combinations with three replications of the centre point) for each formulation.The control over the process and the quality of the resulting pellets were found to depend on the rheological properties of the binders used. In the case of a low viscosity binder (Gelucire^® 50/13), the process was easily controllable whereas in the case of a high viscosity binder (Lutrol^® F68), the process was more difficult to control.The useful yield of the formulation in the case of the low viscosity binder was found to be mostly influenced by the concentration of the binder. On the other hand, different binder concentrations did not affect the useful yield of the formulation prepared by use of the high viscosity binder. In the latter case, mixing time was identified as the variable that mostly influenced the pelletization process.Finally response surface methodology was applied to find the optimum values of the process variables.     

Melted glyceryl palmitostearate (GPS) pellets for protein delivery

Lysozyme was incorporated into glyceryl palmitostearate (GPS) pellets by compression and melting at loadings of 2, 5 and 10% (w/w). Released lysozyme from both compressed and melted pellets showed good retention of enzymatic activity (>80% active). The percentage lysozyme recovered during in vitro release experiments, over 120 h, was significantly lower from the melted pellets (<15%) compared with compressed pellets (71-85%). Scanning electron microscopy suggested this difference in release was due to differences in porosity of the compressed and melted pellets. Inclusion of hydrophilic components, PEG 4000 and Gelucire 50/13, in the melted matrices increased the percentage of lysozyme released in vitro. Lysozyme released from GPS/PEG 4000 matrices showed good retention of enzymatic activity (>88% active) while that from GPS/Gelucire 50/13 showed reduced activity (68 and 51% active). PEG 4000 was not completely miscible with GPS at the concentrations studied and heterogenous systems resulted. At a loading of 20-35% (w/w) PEG 4000 in GPS greater than 80% of the incorporated lysozyme was released, indicating the likely achievement of interconnecting hydrophilic channels throughout the GPS matrix. In conclusion, melted GPS demonstrated potential as a matrix for the controlled release of proteins and release rates could be modified by inclusion of hydrophilic components.     

Effect of the melt granulation technique on the dissolution characteristics of griseofulvin

This work describes a melt granulation technique to improve the dissolution characteristics of a poorly water-soluble drug, griseofulvin. Melt granulation technique is a process by which pharmaceutical powders are efficiently agglomerated by a meltable binder. The advantage of this technique compared to a conventional granulation is that no water or organic solvents is needed. Because there is no drying step, the process is less time consuming and uses less energy than wet granulation. Granules were prepared in a lab scale high shear mixer, using a jacket temperature of 60 degrees C and an impeller speed of approximately 20,000 rpm. The effect of drug loading (2.5/5%), binder (PEG 3350/Gelucire 44/14), filler (starch/lactose), and HPMC on the dissolution of griseofulvin was investigated using a half two level-four factor factorial design. The granules were characterized using powder XRD, DSC and SEM techniques. A significant enhancement in the in vitro dissolution profiles of the granules was observed compared to the pure drug and drug excipient physical mixtures. The factorial design results indicated that higher drug loading and the presence of HPMC reduced the extent of dissolution of the drug, whereas, the presence of starch enhanced the dissolution rate. XRD data confirmed crystalline drug in formulation matrices. DSC results indicated monotectic mixtures of griseofulvin with PEG in the granulated formulations. In conclusion, the results of this work suggest that melt granulation is a useful technique to enhance the dissolution rate of poorly water-soluble drugs, such as, griseofulvin.     

Melt pelletisation of a hygroscopic drug in a high shear mixer. Part 2. Mutual compensation of influence variables.

The process of melt pelletisation in a Diosna P10 high shear mixer was examined for sodium valproate and glycerol monostearate. The effects of binder concentration, impeller speed and massing time on mean granule size, size distribution and liquid saturation were investigated. Spherical pellets of almost similar size and size distribution were obtained after 20 min of massing time, with a binder content from 3.1 to 14.1% w/w by adjusting the impeller speed. Granule growth was observed at low levels of binder concentration and liquid saturation (<80%) which is untypical for melt granulation. The liquid saturation seemed to have no major influence on the final pellet size. Additional, mutually compensating effects on granule growth were found to be impeller speed and massing time for a fixed binder concentration. Low levels of both, binder concentration and impeller speed, allowed for good control of the process. The amount of water adsorbed by the hygroscopic drug was found to accelerate granule growth.     

Effects of interactions between powder particle size and binder viscosity on agglomerate growth mechanisms in a high shear mixer.

A study was performed in order to elucidate the effects of the interactions between powder particle size and binder viscosity on the mechanisms involved in agglomerate formation and growth. Calcium carbonates having mean particle sizes in the range of 5-214 microm and polyethylene glycols having viscosities in the range of approximately 50-100000 mPas were melt agglomerated in a high shear mixer. Agglomerate growth by nucleation and coalescence was found to dominate when agglomerating small powder particles and binders with a low viscosity. Increasing the binder viscosity increased the formation of agglomerates by immersion of powder particles in the surface of the binder droplets. With a larger powder particle size, an increasing binder viscosity was necessary in order to obtain an agglomerate strength being sufficient to avoid breakage. Due to a low agglomerate strength, a satisfying agglomeration of very large particles (214 microm) could not be obtained, even with very viscous binders. The study demonstrated that the optimum agglomerate growth occurred when the agglomerates were of an intermediate strength causing an intermediate deformability of the agglomerates. In order to produce spherical agglomerates (pellets), a low viscosity binder has to be chosen when agglomerating a powder with a small particle size, and a high viscosity binder must be applied in agglomeration of powders with large particles.