Ibuprofen Particles Research Articles

The impacts of roller compaction on the quality attributes of simultaneously compressed micro and minitablets

The challenges of developing good quality low dose minitablets was assessed by systematically studying the effects of ibuprofen (IBU, a model compound) particle sizes (6–58 µm D50) and concentrations (0.1–3 %w/w), roller compaction forces (3–7 kN/cm), and the minitablet sizes (1.2, 1.5 and 2 mm diameter). A novel compression approach, where all three minitablet sizes were simultaneously produced in a single compression run was used. Roller compacted ribbons, granules, minitablets were characterized for physico-mechanical properties and minitablets were also characterized for stratified content uniformity and weight uniformity. The results showed that roll force was the more dominant factor to ribbon solid fraction or tensile strength and granule size enlargement. Minitablets obtained from the granules had good weight uniformity; all but one batch met the <Ph. Eur. 2.9.5 > criteria. The precise control of tooling lengths across the various sizes was found profoundly important for achieving expected weights, solid fraction, and tensile strength of the simultaneously produced minitablets. The roller compaction process considerably improved the CU variability of the minitablets as compared to the direct compression process. Smaller particle size and higher concentration of IBU, increased roller compaction force, and larger minitablet size improved the potency and content uniformity; however, only the minitablet size was a statistically significant factor in this study. As a product strategic design criterion, a threshold of 25 minitablets in a dosage unit would ensure robust downstream filling and weight verification operations as well as dose accuracy and uniformity (would pass <USP 905> stage 1 criteria). This study results demonstrated feasibility of the novel simultaneous compression approach and the roller compaction process in developing good quality minitablets.

Application of shadowgraph imaging (SGI) particle characterisation data to interpret the impact of varying test conditions on powder dissolution and to develop an automated agglomeration identification method (AIM) in the USP flow-through apparatus

The aims of this work were 1) to explore the application of shadowgraph imaging (SGI) as a real time monitoring tool to characterize ibuprofen particle behaviour during dissolution testing under various conditions in the USP 4 flow-through apparatus and 2) to investigate the potential to develop an SGI-based automated agglomeration identification method (AIM) for real time agglomerate detection during dissolution testing. The effect of surfactant addition, changes in the drug mass and flow rate, the use of sieved and un-sieved powder fractions, and the use of different drug crystal habits were investigated. Videos at every sampling time point during dissolution were taken and analysed by SGI. The AIM was developed to characterize agglomerates based on two criteria – size and solidity. All detections were confirmed by manual video observation and a reference agglomerate data set. The method was validated under new dissolution conditions with un-sieved particles. Characterisation of particle dispersion behaviour by SGI enabled interpretation of the impact of dissolution test conditions. Higher numbers of early detections reflected greater dissolution rates with increased surfactant concentration, using sieved fraction or plate-shaped crystals, but was impacted by drug mass tested. An AIM was successfully developed and applied to detect agglomerates during dissolution, suggesting potential, with appropriate method development, for application in quality control.

Auto-agglomeration of dry ibuprofen powder under mechanical vibration: Effect of particle morphology and surface properties

This study investigates the effect of ibuprofen particle morphology and surface properties on its tendency to auto-agglomerate. Four diverse particle morphologies were produced by recrystallisation of ibuprofen from solvents with different polarities. The aspect ratio and the polar component of the recrystallised particles decreased as follows: methanol > ethanol > acetonitrile > hexane. The auto-agglomeration process was induced by mechanical vibration and the agglomerate strength was assessed by the Dispersion and Agglomerate Strength indices. Relatively strong agglomerates were detected only in the case of ibuprofen recrystallised from ethanol and acetonitrile, whereas weaker and no agglomerates were formed during mechanical vibration of ibuprofen recrystallised from methanol and hexane, respectively. It was found that tendency of ibuprofen powder to auto-agglomerate was associated with lower tribo-electric charges during mechanical vibration, hypothetically linked to the competitive advantage of electrostatic attraction of high surface polarity particles to the walls of the vibration box which can hinder particle-particle interactions. Crystal surface polarity could be altered by the crystallisation protocol and/or by particle breakage (exposing more crystal facets of high polarity) during mechanical vibration.

Robust Wet Milling Technique for Producing Micronized Ibuprofen Particles with Improved Solubility and Dissolution

This study investigated a systematic approach for producing ibuprofen (IBF) particles with leucine by wet milling. Using a high shear homogenizer, the particles size of the IBF was reduced. Prepared IBF microparticles were freeze-dried and characterized by using Mastersizer, SEM, DSC, XRD, ATR-FTIR, and TGA. The drug saturation solubility and in-vitro dissolution performance were carried out in phosphate buffer solution (PBS, pH 7.4) at 37°C temperature and IBF were determined using a validated HPLC method. The wet-milled method reduced the particle size from 71.3 to 1.7μm. The minimum particle size of IBF was obtained in 0.05% Tween 80 solution homogenized at 17,000rpm for 15min. The saturated solubility (168.7µg/mL) of the micronized IBF particles with leucine showed higher compared to that of the original IBF (147.4µg/mL) in PBS solution. The prepared IBF particles containing 2.5-6.25% leucine showed significantly higher IBF release (100%) compared to that of original drug particles (55.9%) in 120min. The excipient leucine played a major role in enhancing the solubility and dissolution profile of the prepared IBF particles probably by the formation of hydrogen bonding. The developed wet milling was an efficient and robust technique for reducing the particle size of IBF and could be a useful method for manufacturing drug particles with enhanced solubility and dissolution.

Assessing the effect of moderately increasing medium viscosity on the intrinsic dissolution rate and diffusion coefficient of ibuprofen particles

This study investigated the effects of moderately increasing medium viscosity through two viscosity enhancing agents (VEA) (HPMC and sucrose) on the intrinsic dissolution of a BCS class II drug (ibuprofen). The differences in intrinsic dissolution were characterized through the estimation of a diffusion coefficient (D) of ibuprofen in different media with the Levich equation. Increasing viscosity decreased the intrinsic dissolution rate of ibuprofen with both VEAs. The calculated D from intrinsic dissolution data overestimated the experimental value, but the results suggest that intrinsic dissolution could be used as a tool to estimate a relative change in D in different viscosities.&amp;nbsp;

Level A IVIVC for immediate release tablets confirms in vivo predictive dissolution testing for ibuprofen

A bioequivalence study comparing two fixed dose combination tablets containing 200 mg ibuprofen and 30 mg pseudoephedrine hydrochloride showed bioequivalence for pseudoephedrine AUC and Cmax, but the reference product showed higher Cmax than the test product in fasted conditions. The main difference between products was the presence of tribasic calcium phosphate in the reference tablet, resulting in an increased surface pH of the dissolving ibuprofen particles under gastric and intestinal conditions and, consequently, higher solubility of ibuprofen. A mechanistic model based on mass balance and ionization equilibria was used to calculate the pH of the particle surface under different buffer conditions. The discrepancies in surface pH between test and reference tablet were pronounced in 0.1 M and 0.01 M hydrochloric acid and in diluted maleate 7 mM pH 6.5 and phosphate 5 mM pH 6.7 buffers (but negligible in compendial phosphate buffer pH 6.8. Only those dissolution tests using pre-treatment in acidic conditions could be used to build a one-step in vitro-in vivo correlation (IVIVC). This work shows the potential of these discriminatory and in vivo predictive dissolution methods to obtain IVIVCs for BCS class IIa drugs and for extending BCS biowaivers to BCS class IIa drugs.

Impact of altered hydrophobicity and reduced agglomeration on dissolution of micronized poorly water-soluble drug powders after dry coating

The impact of dry coating with hydrophobic or hydrophilic nano-silica at 25–100% surface area coverage on dissolution of micronized poorly water-soluble drugs was investigated by examining their agglomeration and surface hydrophobicity. Ibuprofen (20 µm and 10 µm) and griseofulvin (10 µm) were selected having differing solubility, hydrophobicity, and surface morphology. Characterization involved particle agglomeration via two dry dispersion methods, drug dissolution using the USP IV method, cohesion reduction through shear testing, and powder wettability via the modified Washburn method. Dry coating dramatically reduced the cohesion hence agglomerate size of both the coated ibuprofen particles, but less for griseofulvin, attributed to its surface morphology. For hydrophobic silica, agglomerate size reduction outweighed the adverse impact of increased surface hydrophobicity for ibuprofen. For griseofulvin, the agglomerate reduction was much lower, not able to overcome the effect of increased drug particle hydrophobicity with hydrophobic silica coating. Hydrophilic silica coating reduced hydrophobicity for all three drug powders, leading to the synergistic improvement in the dissolution along with agglomerate size reduction. Overall, the combined effect of the drug particle surface hydrophobicity and agglomerate size, represented by specific surface area, could explain the dissolution behavior of these poorly water-soluble drugs.

Systemic Review of Screening the Shapes of Ibuprofen Particles in Different Solvents

Ibuprofen is a very popular analgesic which is mostly available in the market as tablet dosage form. The ibuprofen molecule possesses a chiral center in the propionic acid group. So, there are two enantiomers (R and S), whose chemical properties are similar, but which have optical rotations of opposite sign. The (-) form (l- or laevo-) is the R (-) enantiomer whereas the (+) form (d or dextro-) is referred to as S (+) – ibuprofen. The R (-) isomer is biologically inactive while the S (+) isomer is active. The R (-) form however is slowly converted to the S (+) active form during metabolism in the human body by the presence of the enzyme isomerase (2-arylpropionyl-CoA epimerase). Thus, a large difference in the body potency between the two enantiomers is not found.&#x0D; During manufacturing of tablet, ibuprofen particle plays a significant role in flowability and compressibility etc. Theoretically particle size and shape have great impact on those sorts of mechanical properties of tablets. The morphology can influence physical properties such as packing density, bulk density, agglomeration, and dissolution behaviour as well as the mechanical strength and wet ability. Furthermore, crystal shapes have also been found to have an effect on the bioavailability of the resulting APIs. Commercial ibuprofen typically has a needle shaped morphology with rough surfaces and show poor flowability, poor compaction behavior and a tendency to stick to the tablet punches. To overcome these problems, a suitable size and shape of ibuprofen crystal is desirable that could be directly compressed with fewer operation steps but still having good product stability and therapeutic efficacy, but it can be changed through recrystallization or other methods such as spray drying, etc. Ibuprofen crystallized from solvents with a high hydrogen bonding ability like methanol will form chunky crystals and low hydrogen bonding solvents like hexane will form needle like crystals. Therefore, it was necessary to review the shapes of ibuprofen particles in different solvents.&#x0D; This review paper has covered a comprehensive studies of ibuprofen particle shapes in different solvents and cosolvents.

Pressure drop particle precipitation from a quasi-incompressible, ternary and liquid mixture

We found a quasi-incompressible and liquid mixture of ibuprofen, water and acetone, that enables the crystallization of ibuprofen particles by decreasing the pressure from 15MPa to ambient pressure (~0.1MPa). We measured the solubility of ibuprofen in the mixture as a function of the acetone/water-ratio for pressures of 0.1MPa, 5.5MPa and 15MPa and at 308K using the cloud point method. Based on the solubilities, binodal compositions of the ternary system were modelled using the NRTL-SAC model. The solubility of the drug in the mixture increases with increasing pressure at constant acetone/water-ratio. This pressure sensitive solubility can be exploited for the crystallization of ibuprofen particles via a pressure-drop approach. A pressure-drop from 15MPa to ambient pressure ~0.1MPa can result in a supersaturation of up to 1.43.

Selection of Small Amounts of Glidant Capable of Improving the Tensile Strength of Ibuprofen Tablets.

This study examined the selection of small amounts of excipients capable of improving the compactability of ibuprofen, thereby enabling the miniaturization of ibuprofen tablets. Various glidants in amounts of 1% of the total volume were added to dry surface-modified ibuprofen, and the tensile strengths of the resulting tablets were evaluated. The characteristics of the excipients that affected the tensile strengths of the tablets were then extracted using a tensile strength prediction model. We confirmed that the effective angle of the internal friction of the mixed powder, the coating form of the glidant, the packing fraction of the raw material, and the mixed powder affect the tensile strength of the tablet. A smooth particle layer was formed on the surface of the ibuprofen particles when a glidant with a packing fraction of <0.05 was used. In the sample with a smooth particle layer, the angle of the critical state line increased significantly and the tensile strength improved. We inferred that the smoothness of the particle layer allowed the ibuprofen particles to come into close contact with each other. Consequently, the number of junctions increased, and the frictional force between the particles improved, resulting in tablets with improved tensile strengths. In conclusion, the compactability of ibuprofen was improved by adding 1% glidant with a packing fraction of <0.05. The reduction in excipients will allow the creation of smaller tablets, making them easier to swallow. Therefore, the medication adherence of customers will be improved.

Hierarchical Mass Transfer Analysis of Drug Particle Dissolution, Highlighting the Hydrodynamics, pH, Particle Size, and Buffer Effects for the Dissolution of Ionizable and Nonionizable Drugs in a Compendial Dissolution Vessel.

Dissolution is a crucial process for the oral delivery of drug products. Before being absorbed through epithelial cell membranes to reach the systemic circulation, drugs must first dissolve in the human gastrointestinal (GI) tract. In vivo and in vitro dissolutions are complex because of their dependency upon the drug physicochemical properties, drug product, and GI physiological properties. However, an understanding of this process is critical for the development of robust drug products. To enhance our understanding of in vivo and in vitro dissolutions, a hierarchical mass transfer (HMT) model was developed that considers the drug properties, GI fluid properties, and fluid hydrodynamics. The key drug properties include intrinsic solubility, acid/base character, pKa, particle size, and particle polydispersity. The GI fluid properties include bulk pH, buffer species concentration, fluid shear rate, and fluid convection. To corroborate the model, in vitro dissolution experiments were conducted in the United States Pharmacopeia (USP) 2 dissolution apparatus. A weakly acidic (ibuprofen), a weakly basic (haloperidol), and a nonionizable (felodipine) drug were used to study the effects of the acid/base character, pKa, and intrinsic solubility on dissolution. 900 mL of 5 mM bicarbonate and phosphate buffers at pH 6.5 and 37 °C was used to study the impact of the buffer species on drug dissolution. To investigate the impacts of fluid shear rate and convection, the apparatus was operated at different impeller rotational speeds. Moreover, presieved ibuprofen particles with different average diameters were used to investigate the effect of particle size on drug dissolution. In vitro experiments demonstrate that the dissolution rates of both the ionizable compounds used in this study were slower in bicarbonate buffer than in phosphate buffer, with the same buffer concentration, because of the lower interfacial buffer capacity, a unique behavior of bicarbonate buffer. Therefore, using surrogates (i.e., 50 mM phosphate) for bicarbonate buffer for biorelevant in vitro dissolution testing may overestimate the in vivo dissolution rate for ionizable drugs. Model simulations demonstrated that, assuming a monodisperse particle size when modeling, dissolution may overestimate the dissolution rate for polydisperse particle size distributions. The hydrodynamic parameters (maximum shear rate and fluid velocity) under in vitro conditions in the USP 2 apparatus under different rotational speeds are orders of magnitude higher compared to the in vivo situation. The inconsistencies between the in vivo and in vitro drug dissolution hydrodynamic conditions may cause an overestimation of the dissolution rate under in vitro conditions. The in vitro dissolution data supported the accuracy of the HMT for drug dissolution. This is the first drug dissolution model that incorporates the effect of the bulk pH and buffer concentration on the interfacial drug particle solubility of ionizable compounds, combined with the medium hydrodynamics effect (diffusion, convection, shear, and confinement components), and drug particle size distribution.

Gelation behavior, drug solubilization capacity and release kinetics of poloxamer 407 aqueous solutions: The combined effect of copolymer, cosolvent and hydrophobic drug

The study elucidated the combined effect of the formulation parameters (the relative contents of the copolymer (poloxamer 407 (P407)), the cosolvent (isopropyl alcohol), and the hydrophobic drug (ibuprofen)) on gelation, applicative properties, drug solubilization capacity and release kinetics of the P407 aqueous solutions under the common conditions of storage and topical administration. The presence of ibuprofen at a therapeutic concentration of 5% enhanced the increase in micellar volume fraction and allowed the gelation of the liquid solutions at P407 concentrations ≥ 15%. Light microscopy, DSC analysis, and rheological measurements pointed that P407 gels with 15–20% of the copolymer enabled controled precipitation of amorphous ibuprofen particles (≤100 μm) in perimicellar microchannels, while gels with 25–30% of P407 as well as increased relative content of the cosolvent in perimicellar aqueous phase, had capacity for complete ibuprofen solubilization. The dissolution of the drug particles during the in vitro drug release test, maintained the drug concentration gradient between the perimicellar microchannels and the acceptor medium allowing diffusion-based sustained drug release up to 12 h. The gels with completely solubilized drug notably decrease drug release rate and the cumulative amount of the drug released. Harmonization of the investigated formulation parameters was critical to the formulation of P407 gels that could be promising drug delivery systems for sustained percutaneous delivery of the hydrophobic model drug ibuprofen with reduced frequency of administration and improved patient compliance.

Decoding the small size challenges of mini-tablets for enhanced dose flexibility and micro-dosing.

Mini-tablets are an age appropriate dosage form for oral administration to pediatric and geriatric patients, either as individual mini-tablets or as composite dosage units. Smaller size mini-tablets than the commonly used 2mm or larger size would offer more tailored micro-dose delivery of investigational drugs. This work demonstrated drug substance particle size, drug loading and mini-tablet size ranges to achieve acceptable quality attributes of mini-tablets. A platform formulation with 60, 80, and 100μm (particle size D6,3) ibuprofen at 3, 14, and 25% loadings were directly compressed into 1.2, 1.5, 2, and 2.5mm diameter mini-tablets. With an enhanced weight control approach, all the mini-tablet batches except the 1.2mm diameter mini-tablets with 100µm ibuprofen at 3% loading would achieve acceptable content uniformity as individual mini-tablets (USP <905> L2 criteria) and as composite dosage units of five or more mini-tablets (USP <905> L1 criteria). A dissolution method was developed and successfully utilized to evaluate the formulations herein. Small size mini-tablets, small ibuprofen particle size, and low dose (or low ibuprofen loading) enhanced the dissolution performance. In addition, hypothetical scenarios of potential dose flexibility, dose range, dose titration, and excipient burden were discussed. The results of this study provide guidance for development of smaller size mini-tablets that enable dosing as a single or composite dosage unit, reduce excipient burden and leverage dispensing technology to achieve enhanced dosing flexibility and micro-dosing.

Solid-solution fibrous dosage forms for immediate delivery of sparingly-soluble drugs: Part 1. Single fibers.

Solid solutions of sparingly water-soluble drugs and highly water-soluble excipients are widely used for enhancing the drug delivery rate into the blood stream. The basic physico-chemical mechanisms, however, are not well understood. To delineate the mechanisms, therefore, in this work solid-solution fibers are immersed in a small volume of dissolution fluid and the drug concentration is monitored versus time. Two formulations are considered: ibuprofen drug and low-molecular-weight hydroxypropyl methyl cellulose (HPMC) excipient; and ibuprofen and HPMC and polyoxyl stearate (POS) excipients. The fibers dissolved in the dissolution fluid and the drug was released up to three orders of magnitude faster than by ibuprofen particles, yielding a maximum supersaturation in the fluid up to 6.5 in 10-15 minutes. Past the maximum, when the fiber was fully dissolved, the drug concentration gradually decreased to terminal solubility, up to a factor of 10 greater than that of pure ibuprofen. Models suggest that the drug release rate is proportional to the drug concentration at the fiber-fluid interface, which is enhanced due to both supersaturation and solubility-increase. The interface supersaturates because the drug-molecule release rate from the fast-eroding HPMC fibers is greater than the precipitation rate within; the solubility increases proportionally to the concentration of micelle-forming POS. Similarly, the dissolution fluid supersaturates, and due to the presence of POS in the solution the terminal solubility is increased. Thus the solid-solution fibers with dual, low-molecular-weight HPMC-POS excipient enhance the release rate, supersaturation, and solubility of sparingly-soluble drugs, and their delivery rate into the blood stream.

Micronization of Ibuprofen Particles Using Supercritical Fluid Technology.

Most of drugs are only slightly soluble in the circulatory system of the human body. This reduces the efficiency of their use and that is why new ways how to increase their solubility are investigated. One way to improve the solubility of the drug is to reduce its particle size. Conventional techniques such as crushing or grinding usually do not guarantee a narrow particle size distribution, which is required for pharmaceuticals. Application of supercritical fluids, especially of supercritical CO₂, seems to be convenient method for the preparation of pharmaceuticals submicron particles or nanoparticles. The method enables the preparation of particles in a narrow size distribution and at the same time it does not leave any unwanted residues of solvents or other chemicals. The aim of this work is the micronization of ibuprofen particles using the supercritical fluid and characterization of formed products. The micronization of the particles was done using commercially available device Spe-ed SFE-4 in rapid expansion of supercritical solution mode. The applied temperatures and pressures were 308.15 K and 313.15 K and 200, 250 and 300 bar. The prepared particles were characterized using methods of X-ray diffraction, infrared spectroscopy, particle size distribution, scanning electron microscopy and tests of dissolution and permeability. Mean particles size was reduced from 180 μm (original ibuprofen) to 2.8-7.3 μm of the processed samples. The dissolution test confirmed better solubility and the permeability of newly formed particles improved.

Effect of Methylcellulose (Cellulose Derivatives) on Ibuprofen-crushing Efficiency in Nano Pulverizer NP-100

It is expected that drug systems using nanoparticles will improve the problem of poor water solubility and bioavailability of lipophilic drugs. However, it is difficult to prepare the formulations containing nanoparticles, and it is important to determine the concentration and kind of additives to prepare the formulations. We previously reported that a nano pulverizer NP-100 is possible to prepare drug nanoparticles for the 2-3 min, and the cellulose derivatives (metolose®, methylcellulose) is usefulness to prepare the nanoparticles by the mill method. In this study, we investigated the relationships of methylcellulose type and crushing efficiency in NP-100. First, we demonstrated the effect of viscosity in the various methylcellulose on the ibuprofen (IBU, lipophilic drug) particle size, and showed that the viscosity did not relate the crushing efficiency by the NP-100. Next, we measured the changes of cumulative size frequency curve in IBU particles by the combination of the NP-100 and 0.1-2.0% methylcellulose (SM-4, 400 and 4000). The appropriate addition reached IBU nanoparticles, although, the appropriate addition amount of methylcellulose was different in the SM-4 (0.5%), 400 (1.0%) and 4000 (1.2%). In addition, the IBU became meringue-like when subjected to the bead mill method in the less of methylcellulose, and excessive addition of methylcellulose increased the ratio of coarse particle. In conclusion, this results show that the appropriate addition amount of methylcellulose is different in the type of methylcellulose, and these changes of cumulative size frequency curve is useful as index to determine the concentration and type of additives in the nanoparticle production.

Feasibility of Focused Beam Reflectance Measurement (FBRM) for Analysis of Pharmaceutical Suspensions in Preclinical Development.

This study examined the use of focused beam reflectance measurement (FBRM) for qualitative and quantitative analysis of pharmaceutical suspensions with particular application to toxicology supply preparations for use in preclinical studies. Aqueous suspensions of ibuprofen were used as prototype formulations. Initial experiments were conducted to examine the effects of operational conditions including FBRM probe angle, probe location, and mixing (method and rate of mixing) on the FBRM analysis. Once experimental conditions were optimized, the homogeneity and sedimentation-redispersion of particles in the suspensions were assessed. Ibuprofen suspension under continuous agitation was monitored using FBRM for 60h to study particle size change over time. Another study was performed to determine if particle count rates obtained by FBRM could be correlated to suspension concentration. The location and the angle of the FBRM probe relative to the beaker contents, and the rate and the method of mixing the suspension were found to be sensitive parameters during FBRM analysis. FBRM was able to monitor the process of particle sedimentation in the suspension. The attrition of ibuprofen particles was detectable by FBRM during prolonged stirring with an increase in the number of smaller particles and decrease in the number of larger particles. A strong correlation was observed between particle count rate by FBRM and ibuprofen concentration in the suspension. Also, change in content uniformity in the suspension at different locations of the beaker was represented by FBRM particle count. Overall, FBRM has potential to be a useful tool for qualitative and quantitative analysis of pharmaceutical suspensions.

A quality by design (QbD) twin—Screw extrusion wet granulation approach for processing water insoluble drugs

In this study, a Quality by Design (QbD) approach was used to identify the effect of formulation parameters in a twin screw wet extrusion granulation process for the manufacturing of ibuprofen (IBU) granules with increased dissolution rates. A fractional factorial Design of Experiment (DoE) was used to investigate the effect of the excipient composition, binder amount and liquid to solid (L/S) ratio (independent variables) on drug dissolution rates, median particle size diameter and specific surface area (dependent variables). The intra-granular addition of the binder in inorganic/polymer blends processed with ethanol as granulating liquids facilitated the formation of granules at various particle sizes. DoE regression analysis showed that all formulation parameters affect the dependent variables significantly. The enhanced dissolution rates were attributed not only to the IBU particle size reduction and adsorption in the porous inorganic network but also to the high specific surface area of the produced granules. Dynamic vapour sorption showed increased water absorption for granules with small particle size distribution and high specific surface area.

Implementation of design of experiments approach for the micronization of a drug with a high brittle–ductile transition particle diameter

Objective: To optimize air-jet milling conditions of ibuprofen (IBU) using design of experiment (DoE) method, and to test the generalizability of the optimized conditions for the processing of another non-steroidal anti-inflammatory drug (NSAID).Methods: Bulk IBU was micronized using an Aljet mill according to a circumscribed central composite (CCC) design with grinding and pushing nozzle pressures (GrindP, PushP) varying from 20 to 110 psi. Output variables included yield and particle diameters at the 50th and 90th percentile (D50, D90). Following data analysis, the optimized conditions were identified and tested to produce IBU particles with a minimum size and an acceptable yield. Finally, indomethacin (IND) was milled using the optimized conditions as well as the control.Results: CCC design included eight successful runs for milling IBU from the ten total runs due to powder “blowback” from the feed hopper. DoE analysis allowed the optimization of the GrindP and PushP at 75 and 65 psi. In subsequent validation experiments using the optimized conditions, the experimental D50 and D90 values (1.9 and 3.6 μm) corresponded closely with the DoE modeling predicted values. Additionally, the optimized conditions were superior over the control conditions for the micronization of IND where smaller D50 and D90 values (1.2 and 2.7 μm vs. 1.8 and 4.4 μm) were produced.Conclusion: The optimization of a single-step air-jet milling of IBU using the DoE approach elucidated the optimal milling conditions, which were used to micronize IND using the optimized milling conditions.

Continuous low-dose feeding of highly active pharmaceutical ingredients in hot-melt extrusion

Context: Manufacturing solid low-dose pharmaceutical products has always the homogeneity challenge. In continuous manufacturing, there is the additional challenge of feeding active pharmaceutical ingredient (API) dry powder at low rates. This paper presents a method for feeding API particles into a continuous extrusion process using a suspension. The challenges for feeding and the product homogeneity are both addressed.Objective: The objective of this study is to demonstrate the feasibility of manufacturing low-dose extrudates by feeding the API particles in a diluted anti-solvent suspension.Materials and methods: Extrudates with an Ibuprofen content of 0.021% and 0.043% (w/w) were prepared by feeding a 0.9% w/w suspension of Ibuprofen particles into a Coperion extruder.Results and discussion: The homogeneity (RSD) of extrudates was tested during a time span of 30 min and had values between 2% and 7%.Conclusion: Feeding particles in an anti-solvent suspension offers a simple feeding option for API and minor components which yield products of desired homogeneity. The liquid feeding approach offers a simplified process with enhanced process control possibilities.