Granulating Fluid Research Articles

Formulation and Evaluation of Controlled Release Floating Microballoons of Stavudine.

The aim of this study was to formulate and evaluate stavudine floating microballoons for controlled drug release. Initially, the drug-loaded low-density granular pellets were prepared with hydroxypropyl methylcellulose E5 grade and by using isopropyl alcohol as a granulating fluid. Further, the low-density granular pellets were subjected to microencapsulation by an emulsion evaporation technique using ethyl cellulose 7 cps and Eudragit S 100 as coating polymers and 1% w/v polyethylene glycol 400 as aqueous phase. The prepared microballoons were characterized for their particle size analysis, angle of repose, and compressibility index. The in vitro release studies were performed in 0.1 N HCl as medium. The prepared microballoons were free-flowing and spherical in shape. From all the formulations, F5E and F5F can be considered as promising controlled release floating microballoons of stavudine providing first-order release over a period of 12 hours, with a minimum floating lag time of 1 minute. It was found that the ratio of the drug & polymer, stirring speed, and concentration of surfactant were the most significant variables which influenced the size of the stavudine microballoons under the applied experimental conditions.

A new methodology for high drug loading wet granulation formulation development

A new methodology that enables efficient and rapid development of high drug load (>85%) high shear wet granulation formulations is proposed and tested in this work. Correlations between the API properties, the binder types, the granulation fluid levels, and the product attributes revealed in course of the study are discussed. The key feature of the methodology is that an excipient is added to the formulation only when it is demonstrated that it is required to improve processability or performance of the formulation. To evaluate this approach, three compounds: simvastatin, etoricoxib, and metformin hydrochloride were selected as model drug substances. These compounds differ significantly with respect to their particle size distributions, wettability, and solubility. The compounds were granulated using a range of granulation fluid levels, with or without a polymeric binder. Granule size distribution, strength, flowability, dissolution, and compactibility were characterized. Select granulations were further compressed into tablets, both "as-is" and with addition of extragranular excipients. One formulation was also investigated in an in vivo dog PK study. The study demonstrated that using the methodology, high drug load formulations with satisfactory attributes could be successfully developed for all three model compounds. Applicability and benefits of the proposed methodology are discussed.

Rheology of pharmaceutical granulations.

The rheological transformations that take place when granulating fluid is added to pharmaceutical powders have been monitored by means of a laboratory scale (approx. 50 g amounts) torque rheometer. The three formulations studied, based on lactose, sulfadiazine, and benoxaprofen, had common characteristics in that each passed through a granulation peak of maximum torque. In the zone immediately before the peak the granules were growing, while after it the material had properties of a cohesive, viscoelastic mass. Therefore, the rheological state of the material under process is not specified by a single torque reading, but by the rheological history of the granulation.

The use of response surface methodology for the formulation and optimization of salbutamol sulfate hydrophilic matrix sustained release tablets

The objective of this study was to develop a hydrophilic matrix formulation with in vitro release characteristics similar to Asthalin® tablets and that would sustain the release of salbutamol sulfate over a 12-h period. A central composite design was used as the framework for manufacturing formulations that may be used to understand the relationships between polymer levels and in vitro release characteristics. Tablets were manufactured using wet granulation with Surelease® as the granulating fluid and different levels of Methocel® K100M, xanthan gum, and Carbopol® 974P as matrix-forming materials. In vitro dissolution testing was conducted using USP Apparatus 3 and samples were analyzed using a validated reversed-phase HPLC method. The results revealed that the levels and types of polymers had a significant impact on the rate of drug release from these formulations and that it was possible to optimize the levels of matrix-forming polymers to achieve the desired release characteristics. Statistical design and response surface methodology have been successfully used to understand and optimize formulation factors and interactions that impact the in vitro release characteristics of salbutamol sulfate from a potential multisource sustained release dosage form.

Effect of formulation hydrophobicity on drug distribution in wet granulation

Wet granulation is a process of enhancing the powder properties by producing larger particles from the agglomeration of agitated fine particles with liquid. The production of enlarged “granules” is often carried out in high-shear granulators, an equipment item prevalent in the pharmaceutical and food industries. In the pharmaceutical industry, good wettability between the liquid binder and the powder components in the formulation are relied upon to produce strong granules with a narrow size distribution. The wettability of hydrophobic drugs in the formulation is often improved by the use of surfactants; but this may not always be possible. Previous work on heterogeneous-wetting granulation [1–3] has found that as the formulation hydrophobicity increases, the average granule size decreases. The decreasing proportion of hydrophilic component available for granulation may influence the decreasing average granule size, however an explanation for this has not been clearly proposed. The observation and reasoning behind the granulation behaviour for heterogeneous-wetting powders forms the basis of this paper. Granulation experiments were carried out on varying degrees of formulation hydrophobicity and the granulation batch is sieved into different size fractions for sieve fraction assay analysis to determine the average granule composition and the drug distribution throughout the granulation batch. The sieve fraction assay analysis revealed that the drug distribution in the granular batch is strongly dependent upon the formulation wettability. This was seen for batches with water as the granulating fluid where the drug distribution was uneven and resulted in some sieve fractions being enriched or deficient of drug content. When the wettability of the formulation was improved a more uniform distribution of drug was achieved across all sieve fractions and formulation hydrophobicity. The average granule size decreased as the formulation hydrophobicity increased, supporting previous works, and this is due to the decreasing liquid bridge strength between the particles.

Multivariate optimization of formulation and process variables influencing physico-mechanical characteristics of site-specific release isoniazid pellets

In the present study, isoniazid was formulated as site-specific release pellets with high drug loading (65%, w/w) using extrusion-spheronization followed by aqueous coating of Sureteric ® (35% weight gain). A statistical experimental strategy was developed to optimize simultaneously the effect of the two formulation variables and one process variable on the critical physico-mechanical properties of the core pellets of isoniazid. Amount of granulating fluid and amount of binder were selected as formulation variables and spheronization speed as a process variable. A 2 3 full factorial experimental design was employed for the present study. Pellets were characterized for physico-mechanical properties viz. usable yield, pellet size, pellips, porosity, abrasion resistance, mechanical crushing force, residual moisture and dissolution efficiency. Graphical and mathematical analysis of the results allowed the identification and quantification of the formulation and process variables active on the selected responses. A polynomial equation fitted to the data was used to predict the responses in the optimal region. The optimum formulation and process parameters were found to be 44.24% (w/w) of granulating fluid, 2.13% (w/w) of binder and spheronization speed of 1000 rpm. Optimized formulation showed usable yield 84.95%, particle size 1021.32 μm, pellips 0.945, porosity 46.11%, and abrasion resistance 0.485%. However, mechanical crushing force, residual moisture and dissolution efficiency were not significantly affected by the selected independent variables. These results demonstrate the importance of, amount of water, binder and spheronization speed, on physico-mechanical characteristics of the isoniazid core pellets with high drug loading.

Development and Evaluation of Enteric Coated Tablet Containing Diclofenac Sodium

The influence of various polymers on the release rate of Diclofenac Sodium from enteric coated tablets was investigated in an attempt to formulate a delayed release solid dosage forms. Prepared the conventional diclofenac sodium tablets by wet granulation method (non-aqueous) using granulating fluid (isopropyl alcohol). Developed the aqueous coating formula using shacryl and non-aqueous coating formula using HPMCP and optimized the best aqueous coating formula. Coating was performed in a mini coating pan at 107 rpm using low-pressure air atomized liquid spray techniques. Comparative dissolution, disintegration and antiulcer studies were performed on the best products and marketed products. The Comparative antiulcer studies were performed on wister albino rats using conventional, dummy and enteric-coated tablets.

Formulation of a solid intravaginal matrix system to prolong the pH-decreasing effect of lactic acid

The aim of our work was to study the applicability of solid matrix systems for the formulation of long-acting intravaginal tablets containing lactic acid. These systems were compressed from matrix granules containing hydroxypropylmethyl cellulose (HPMC), lactose monohydrate and microcrystalline cellulose (MCC, the binder and carrier of lactic acid) as additives. The active pharmaceutical ingredient (API) was incorporated into the granulating fluid and the effect of its concentration (evaluated up to 15%) on the pH-decreasing effect of the tablets was assessed. The particle size and mechanical properties of the granules did not change relevantly. The dissolution of the active component (change in H + concentration) was tested with a modified dissolution test for 8 h. The pH-decreasing effect of tablets was influenced by the lactic acid content. It was the highest for samples containing the largest amount of lactic acid. The cumulative concentration of dissolved H + was plotted, which curve exhibited a break at about 4 h. Up to this time, the shape of the tablets constantly changed (a hemisphere was formed) at every sample, after this time no change in shape could be detected. It can be concluded that in the first stage of dissolution erosion was the main factor influencing the liberation of the API. This is necessary for the detachment of lactic acid from the insoluble MCC. A relatively quick liberation was detected in the initial period (0–4 h) for the samples containing a small amount of lactic acid, which can be explained by the simpler liberation of API. Below 9% lactic acid, the readier liberating sites of the carrier were saturated. In the later stage of dissolution (5–8 h), the slower processes were more relevant. Additionally, it can be stated that the composition applied was appropriate for the formulation of a long-acting matrix system containing lactic acid.

Evaluation of the binding effect of human serum albumin on the properties of granules

The main objective of this study was the application of a solution of human serum albumin as a granulating fluid. The properties of the granules formed were evaluated and compared with those when a conventional binder was applied in the same concentration. The powder mixture contained a soluble (mannitol) and an insoluble component (different types of cellulose). The protein solution applied exerted an appropriate aggregating effect if the system contained microcrystalline celluloses. Powdered cellulose was not suitable for the granulation with human serum albumin solution. As compared with the same concentration of the conventionally applied cellulose ethers as binder, the prepared granules exhibited a larger particle size, a significantly better compressibility, a higher breaking hardness and a favourable deformation process. These findings mainly reflect the good adhesive properties of the protein. The best compressibility and mechanical behaviour were attained on the application of the microcrystalline cellulose Vivapur type 105. This favourable behaviour may be connected with the wettability of cellulose. These results suggest that the formulation of tablets may be easier from an active agent in the serum that binds to albumin (e.g. interferon) since the amount of additives (binder) can be reduced.

Agglomeration of hydrophobic powders via solid spreading nucleation

Wet granulation of a highly hydrophobic fine powder was investigated to elucidate the granule nucleation and growth processes in systems in which distribution of granulating fluid in the granulating mass is complicated by poor wetting. A mixture containing approximately 70 wt.% (90% by volume) of a micronized poorly wetting powder was granulated in a high-shear mixer using water and the microstructure of resultant agglomerates (granules) was studied using optical and electron microscopy as well as X-ray computed tomography (XRCT). The study revealed that granules are typically spherical or elliptical in shape and range in size from 200 to 500 μm. They are strong and consist of a consolidated powder shell and an empty core. Based on the microstructure, a nucleation mechanism for such a hydrophobic system is proposed. Implications for controlling granule growth and granule properties are discussed. This study demonstrates that well-controlled nuclei formation and subsequent granule growth is achievable in a highly hydrophobic system.

Masking of Unpleasant Gustatory Sensation by Cross-Linking of Dehydrated Paracetamol Alginate Pellets Produced by Extrusion-Spheronization

Alginate paracetamol pellets were prepared by extrusion-spheronization process. The process variables studied were wet mass mixing time, feed rate, die opening diameter, spheronization residence time, feed rate, disk speed, and drying. The formulation variables studied were granulation fluid composition and level and drug-to-excipient ratios. The dried pellets were cross-linked with calcium chloride solution. The cross-linked pellets were evaluated for dissolution test, friability test, sphericity, flow behavior, particle size distribution, aggregation, water uptake, drug entrapment, and yield. Gustatory sensation test exhibited successful taste-masking of paracetamol by present approach.

The effect of wetting of powder mixture on the preparation of hydrophilic matrix granules with high-shear granulator

The aim of our work was to determine the main factors which can influence the preparation of matrices and to choose the best parameters for the production of inert matrix granules with a high-shear granulator. Matrices were formulated, which contained hydroxypropyl methylcellulose (HPMC) as a matrix-forming agent, together with lactose monohydrate and microcrystalline cellulose as filler. There was a good correlation between the erosion time of the matrix comprimates and the water uptake of the different powder mixtures. The powder mixtures containing at least 40% of HPMC exhibited very similar properties to those of pure HPMC. Granules were prepared from the powder mixture with 30% of HPMC. The optimum amount of granulating fluid (water) was determined according to the quantity of the particles with optimum size. A 2 4 full factorial design was used to determine the operational parameters of the granulation for this composition. A significantly lower amount of waste was attained with a long spheronization time and slow dosing. The gel-forming properties of the HPMC, and hence the slower wettablity mean that the most important factors are those that affect the wettability of the powder mixture, and thus the factors which increase the time of wetting are relevant during the formulation of this matrix system. There was a relationship between the wetting of the powder mixture and forming of granules prepared with high-shear granulator.

Utilization of a Modified Special‐Cubic Design and an Electronic Tongue for Bitterness Masking Formulation Optimization

A unique modification of simplex design was applied to an electronic tongue (E-Tongue) analysis in bitterness masking formulation optimization. Three formulation variables were evaluated in the simplex design, i.e. concentrations of two taste masking polymers, Amberlite and Carbopol, and pH of the granulating fluid. Response of the design was a bitterness distance measured using an E-Tongue by applying a principle component analysis, which represents taste masking efficiency of the formulation. The smaller the distance, the better the bitterness masking effect. Contour plots and polynomial equations of the bitterness distance response were generated as a function of formulation composition and pH. It was found that interactions between polymer and pH reduced the bitterness of the formulation, attributed to pH-dependent ionization and complexation properties of the ionic polymers, thus keeping the drug out of solution and unavailable to bitterness perception. At pH 4.9 and an Amberlite/Carbopol ratio of 1.4:1 (w/w), the optimal taste masking formulation was achieved and in agreement with human gustatory sensation study results. Therefore, adopting a modified simplex experimental design on response measured using an E-Tongue provided an efficient approach to taste masking formulation optimization using ionic binding polymers.

Fast and Controlled Release of Triamcinolone Acetonide from Extrusion-Spheronization Pellets Based on Mixtures of Native Starch with Dextrin or Waxy Maize Starch

Pellets composed chiefly of inexpensive starches allow modulation of the rate of release of the poorly soluble drug triamcinolone acetonide in media of pH 1.2–6.8. Wheat- or maize-starch-based pellets with 20% of white dextrin release the drug in vitro almost completely within 20 min, while maize-starch-based pellets with 5–35% of waxy maize starch sustain gradual release over periods of 9–12 hr or longer when prepared using appropriate amounts of granulation fluid.

Phase transformations of erythromycin A dihydrate during pelletisation and drying

An at-line process analytical approach was applied to better understand process-induced transformations of erythromycin dihydrate during pellet manufacture (extrusion–spheronisation and drying process). The pellets contained 50% (w/w) erythromycin dihydrate and 50% (w/w) microcrystalline cellulose, with purified water used as a granulating fluid. To characterise changes in solid-state properties during processing, near infrared (NIR) spectroscopy and X-ray powder diffraction (XRPD) were applied. Samples were taken after every processing step (blending, granulation, extrusion, and spheronisation) and at predetermined intervals during drying at 30 or 60 °C. During pelletisation and drying at 30 °C no changes occurred. Partial transformation to the dehydrated form was observed for the pellets dried at 60 °C by NIR and XRPD. The variable temperature XRPD measurements of the wet pellets (from 25 to 200 °C) also confirmed the change to erythromycin dehydrate at approximately 60 °C.

Evaluation of Rate of Swelling and Erosion of Verapamil (VRP) Sustained-Release Matrix Tablets

ABSTRACTTablets manufactured in-house were compared to a marketed sustained-release product of verapamil to investigate the rate of hydration, erosion, and drug-release mechanism by measuring the wet and subsequent dry weights of the products. Swelling and erosion rates depended on the polymer and granulating fluid used, which ultimately pointed to their permeability characteristics. Erosion rate of the marketed product was highest, which suggests that the gel layer that formed around these tablets was weak as opposed to the robust and resistant layers of test products. Anomalous and near zero-order transport mechanisms were dominant in tests and commercial product, respectively.

Formulation of rate-modulating pellets for the release of ibuprofen: An extrusion–spheronization process

Purpose: To develop a stable and reproducible modified release pellet formulation containing ibuprofen.Methods: Using extrusion–spheronization technology to produce pellets.Results: The percentage yield, size distribution and overall pellet shape within the desired size range of 1000–1400 µm was found to be dependent on various process variables. These include extrusion and spheronization speed, spheronization time and composition of the granulation fluid. Formulation factors such as viscosity grade of hydroxypropylmethylcellulose and concentration of microcrystalline cellulose were shown to influence the drug release rate of the pellets. In vitro dissolution studies revealed that the pellets behaved in a pH-dependent manner. Pellets exposed to different drying techniques exhibited an increase in drug release rate in the order corresponding to oven-dried, vacuum-dried, fluid bed-dried and freeze-dried pellets. In conjunction with scanning electron microscopy, kinetic modelling and statistical treatment of dissolution data, it was confirmed that the predominant release rate-controlling mechanism was diffusion, as evidenced from the power law expressions incorporating Fickian and relaxational parameters (Mt /M∞ = K1tn; Mt /M∞ = K1tn + K2t2n). Matrix swelling and erosion were not significant factors in modulating the drug release rate.Conclusions: The pH-dependent property of the pellets may be strategically employed towards development of a site-specific drug delivery system for non-steroidal anti-inflammatory agents. In general, targeting the delivery of an agent with potential for gastric irritation to the proximal intestine/colon may effectively reduce its ulcerogenic effect and ultimately contribute towards improved patient compliance.

Evaluation of extrusion/spheronisation, layering and compaction for the preparation of an oral, multi-particulate formulation of viable, hIL-10 producing Lactococcus lactis

Three formulation techniques were compared in order to develop a multi-particulate formulation of viable, interleukin-10 producing Lactococcus lactis Thy12. First, freeze-dried L. lactis was compacted into mini-tablets. Next, liquid L. lactis culture was used as the granulation fluid for the production of pellets by extrusion/spheronisation. Finally, liquid L. lactis culture was layered on inert pellets as an alternative technique for the production of pellets. L. lactis viability and interleukin-10 production was evaluated. Viability dropped to 15.7% after compaction of freeze-dried L. lactis and to 1.0% after pelletisation of liquid L. lactis by extrusion/spheronisation. The viability in the mini-tablets and pellets, stored for 1 week at RT and 10% RH was reduced to 23 and 0.5% of initial viability, respectively. Storage for 1 week at RT and 60% RH resulted in complete loss of viability. Layering of L. lactis on inert pellets resulted in low viability (4.86%), but 1 week after storage at RT and 10% RH, 68% of initial viability was maintained. Increasing product temperature and cell density of L. lactis in the layering suspension did not significantly change viability after layering and storage. Interleukin-10 production capacity of L. lactis Thy12 was maintained after layering.

Comparison of Low Shear, High Shear, and Fluid Bed Granulation During Low Dose Tablet Process Development

Three processing methods were compared to develop a low dose (0.1%) immediate release tablet. Similar formulations were used to evaluate low shear, high shear, and fluid bed granulation methods. For each granulation process, the drug was dissolved or suspended in the granulating fluid and sprayed into the granulator. Both water and methanol were evaluated as granulating fluids. The low shear granulation was performed in a Patterson‐Kelley V‐Blender with I‐bar. The high shear granulation was performed in a GRAL (top entry impeller) and a Diosna (bottom mounted impeller). Fluid bed granulation was also performed using top‐spray. Acceptable content uniformity was obtained using each technology. The type of granulator and granulating solvent affected the granulation particle size distributions and bulk/tap densities. However, the addition of extragranular microcrystalline cellulose minimized the effect of variable granulation properties and allowed similar tablets to be produced from each granulation process.

Extruded and Spheronized Beads Containing No Microcrystalline Cellulose: Influence of Formulation and Process Variables

The purposes of this study were to investigate the use of chitosan in the manufacture of beads by extrusion‐spheronization without inclusion of microcrystalline cellulose, and to study the effect of formulation and process variables on the characteristics of the beads. Beads containing chitosan, fine particle ethylcellulose, hydroxypropyl methylcellulose (HPMC), and caffeine as the model drug were manufactured. Bead size, yield, shape, friability, density, porosity, and release studies were determined. Spherical beads with good mechanical properties could be manufactured without microcrystalline cellulose. Release studies showed that there was immediate release of drug from the beads. A five factor, half fraction screening design was employed to study the effect of formulation variables and process variables on the properties of the beads. Statistical analysis indicated that formulation variables such as the chitosan content, HPMC content, and water content, and process variables such as the spheronizer speed and extruder speed significantly affected the physical properties of the beads. The bead size decreased with an increase in chitosan content. Significant two‐factor interactions exist between the variables for several of the measured responses. Beads with high percentage yield and high sphericity can be obtained at high chitosan content, and low HPMC content, water content, spheronizer speed, and extruder speed. Less friable beads can be obtained at high levels of studied formulation variables and low levels of studied process variables. Beads of high density and low porosity can be manufactured at high levels of the studied formulation and process variables. Regression equations were generated using Statgraphics Plus software that can be used to develop formulations with desired bead properties. Chitosan was useful to provide beads of acceptable physical properties using water as a granulating fluid in the extrusion‐spheronization process.