Excipient Particles Research Articles

Relationship between Hydrogen-bond Conditions of Surface Adsorbed Water and Interparticle Binding Force on Pharmaceutical Tablets.

Influence of water contents to the pharmaceutical tablet strength is known empirically, and participation of hydrogen bonding force among adsorbed water molecules has been presumed. However, the detailed mechanisms of hydrogen bonding phenomena have not been reported. In this study, the hydrogen bonds states of the surface adsorbed waters on the excipient particles of the tablets were focused upon, and the relationship to the interparticle binding force determined by the Rumpf equation was discussed using a near-infrared spectroscopy (NIR). As for the results, NIR peaks of OH groups of surface water were shifted by a humidity change, and the degrees of the peak shifts correlated to interparticle binding force.

An investigation into the effects of excipient particle size, blending techniques and processing parameters on the homogeneity and content uniformity of a blend containing low-dose model drug.

Powder blend homogeneity is a critical attribute in formulation development of low dose and potent active pharmaceutical ingredients (API) yet a complex process with multiple contributing factors. Excipient characteristics play key role in efficient blending process and final product quality. In this work the effect of excipient type and properties, blending technique and processing time on content uniformity was investigated. Powder characteristics for three commonly used excipients (starch, pregelatinised starch and microcrystalline cellulose) were initially explored using laser diffraction particle size analyser, angle of repose for flowability, followed by thorough evaluations of surface topography employing scanning electron microscopy and interferometry. Blend homogeneity was evaluated based on content uniformity analysis of the model API, ergocalciferol, using a validated analytical technique. Flowability of powders were directly related to particle size and shape, while surface topography results revealed the relationship between surface roughness and ability of excipient with high surface roughness to lodge fine API particles within surface groves resulting in superior uniformity of content. Of the two blending techniques, geometric blending confirmed the ability to produce homogeneous blends at low dilution when processed for longer durations, whereas manual ordered blending failed to achieve compendial requirement for content uniformity despite mixing for 32 minutes. Employing the novel dry powder hybrid mixer device, developed at Aston University laboratory, results revealed the superiority of the device and enabled the production of homogenous blend irrespective of excipient type and particle size. Lower dilutions of the API (1% and 0.5% w/w) were examined using non-sieved excipients and the dry powder hybrid mixing device enabled the development of successful blends within compendial requirements and low relative standard deviation.

Heterogeneous Crystallization Inside Microporous Polymer Particles as a Process Intensification Technology for the Manufacture of Drug Formulations

Current pharmaceutical manufacturing practices lack the type of rapid advancements achieved through the quick adoption of technical innovations as has been done in other manufacturing sectors. There is significant interest from both academia and the pharmaceutical industry in developing new technologies that accelerate process optimization in a cost-effective manner. Process intensification technologies (PITs) improve efficiency and reduce costs by reducing the number of unit operations required to manufacture a drug formulation. Recent studies have shown the potential of directly crystallizing drug compounds inside porous excipients as a PIT for pharmaceutical manufacturing. However, these studies have primarily focused on developing techniques for crystallizing the drug inside the excipients and maximizing drug loading. There is little understanding of how the excipient particles themselves influence the crystallization process or how this technology compares with other drug encapsulation processes. This investigation considers two other drug encapsulation processes, direct crystallization onto nonporous particles and molecular adsorption of the drug. We discuss the direct crystallization of acetaminophen and sulfathiazole inside microporous particles of alginate and carboxymethyl cellulose. The polymer chemistry and available surface area have a significant impact on drug loading and secondary nucleation in the bulk solution. Direct crystallization offers higher drug loadings compared to other drug encapsulation technologies. This study highlights the potential of direct crystallization inside excipients as a PIT for pharmaceutical manufacturing.

A New Role of Fine Excipient Materials in Carrier-Based Dry Powder Inhalation Mixtures: Effect on Deagglomeration of Drug Particles During Mixing Revealed.

The potential of fine excipient materials to improve the performance of carrier-based dry powder inhalation mixtures is well acknowledged. The mechanisms underlying this potential are, however, open to question till date. Elaborate understanding of these mechanisms is a requisite for rational rather than empirical development of ternary dry powder inhalation mixtures. While effects of fine excipient materials on drug adhesion to and detachment from surfaces of carrier particle have been extensively investigated, effects on other processes, such as carrier-drug mixing, capsule/blister/device filling, or aerosolization in inhaler devices, have received little attention. We investigated the influence of fine excipient materials on the outcome of the carrier-drug mixing process. We studied the dispersibility of micronized fluticasone propionate particles after mixing with α-lactose monohydrate blends comprising different fine particle concentrations. Increasing the fine (D<10.0μm) excipient fraction from 1.84 to 8.70% v/v increased the respirable drug fraction in the excipient-drug mixture from 56.42 to 67.80% v/v (p<0.05). The results suggest that low concentrations of fine excipient particles bind to active sites on and fill deep crevices in coarse carrier particles. As the concentration of fine excipient particles increases beyond that saturating active sites, they fill the spaces between and adhere to the surfaces of coarse carrier particles, creating projections and micropores. They thereby promote deagglomeration of drug particles during carrier-drug mixing. The findings pave the way for a comprehensive understanding of contributions of fine excipient materials to the performance of carrier-based dry powder inhalation mixtures.

The SeDeM Expert Diagram System: Its performance and predictability in direct compressible formulations containing novel excipients and different types of active ingredients

The SeDeM Expert Diagram System is a galenic pre-formulation system, which evaluates the suitability of excipients and active pharmaceutical ingredients (API's) for direct compression into tablets as well as predicting possible formulations (i.e. ratios of API:excipient) to obtain acceptable direct compressible tablets. In this study, the prediction ability of the SeDeM Expert Diagram System with a special focus on testing the limits of the system was investigated. Three different active pharmaceutical ingredients (API's) in combination with a mix of classic and novel excipients which are currently in use in the wider pharmaceutical community were utilized. The API's and seven excipients were selected based on their physicochemical properties in order to determine the system's ability to predict ratios of API:excipient for acceptable direct compression tablets (e.g. acceptable weight variation as well as sufficient strength to withstand handling). Predicted formulations were tableted and evaluated according to the set criteria. If a tablet formulation failed to meet the criteria, the ratio of excipient to API was increased in 5% increments until a successful formulation was obtained, while the reverse was applied if a formulation was successful. The SeDeM Expert Diagram System proved to be proficient at predicting acceptable tablet formulations, with a few exceptions. The SeDeM system gave successful predictions for only two excipients (FlowLac® 100 and StarLac®) in the case of paracetamol as API. Contrary to predictions by SeDeM for paracetamol, drug loads between 15 and 30% were prepared depending on the excipient. This may be attributed to the ability of the novel excipients to compensate for the elastic properties of paracetamol. With regard to furosemide, none of the predicted formulations rendered acceptable tablets. This could be attributed to the cohesive properties of furosemide forming interactive mixtures with the excipient particles being coated by the relatively small furosemide particles (86.77%<50μm) imparting poor flow to the powder particles. In the case of pyridoxine, most of the formulations were predicted acceptable. This work indicates that in cases where the predicted formulation proved to be unsuccessful, by following an increment wise step-up in excipient:API ratio as formulation approach, it is possible to identify an acceptable formulation saving valuable time spent on formulation by a trial and error approach.

Direct and model-free detection of carbohydrate excipients in traditional Chinese medicine formula granules by ATR-FTIR microspectroscopic imaging.

A formula granule is a traditional Chinese medicine preparation made from the decoction of a single herbal medicinal. Because of the flexibility for combination and the convenience for utilization, formula granules are becoming popular in clinical applications. However, the efficacy and safety of commercial formula granules often suffer from the improper addition of carbohydrate excipients. Therefore, the detection of carbohydrate excipients is indispensable for the quality control of formula granules. FTIR spectroscopy has been used for the detection of carbohydrate excipients in formula granules. But the overlapped absorption signals limit the sensitivity and specificity of detection. Besides, a large number of multivariate calibration models are needed for quantitative determination. To overcome the above disadvantages, this research utilizes FTIR microspectroscopy for the model-free and universal detection of carbohydrate excipients in formula granules. Using ATR-FTIR imaging, excipient particles and herbal extract particles in formula granules can be measured individually, which resolves the absorption signals of excipients and herbal extract spatially and thus improves the sensitivity and specificity of detection. The content of excipients can be estimated directly from the number of excipient particles, which is robust to the variations of herb extracts and free of calibration models. The case study of Gardeniae Fructus formula granules shows the potential of FTIR microspectroscopy in the direct and rapid detection of carbohydrate excipients in formula granules. Graphical Abstract Excipient particles in TCM formula granules can be measured and recognized individually by FTIR microspectroscopy.

Novel Polyurethane Matrix Systems Reveal a Particular Sustained Release Behavior Studied by Imaging and Computational Modeling.

The aim of the present work was to better understand the drug-release mechanism from sustained release matrices prepared with two new polyurethanes, using a novel in silico formulation tool based on 3-dimensional cellular automata. For this purpose, two polymers and theophylline as model drug were used to prepare binary matrix tablets. Each formulation was simulated in silico, and its release behavior was compared to the experimental drug release profiles. Furthermore, the polymer distributions in the tablets were imaged by scanning electron microscopy (SEM) and the changes produced by the tortuosity were quantified and verified using experimental data. The obtained results showed that the polymers exhibited a surprisingly high ability for controlling drug release at low excipient concentrations (only 10% w/w of excipient controlled the release of drug during almost 8h). The mesoscopic in silico model helped to reveal how the novel biopolymers were controlling drug release. The mechanism was found to be a special geometrical arrangement of the excipient particles, creating an almost continuous barrier surrounding the drug in a very effective way, comparable to lipid or waxy excipients but with the advantages of a much higher compactability, stability, and absence of excipient polymorphism.

Applying surface energy derived cohesive–adhesive balance model in predicting the mixing, flow and compaction behaviour of interactive mixtures

ObjectiveIn this study, we investigated the applicability of cohesive–adhesive balance (CAB) model to predict the interactive mixing behaviour of small excipient particles. Further, we also investigated the application of this CAB model to predict the flow and compactibility of resultant blends. MethodsExcipients created by co-spraying polyvinylpyrrolidone (PVP, a model pharmaceutical binder) with various l-leucine concentrations were used for this study. Paracetamol was used as model active pharmaceutical ingredient (API). The surface energy was used to derive the work of cohesion (wco) and work of adhesion (wad) to predict the interactive mixing behaviour of the excipients with paracetamol. The blends were visualised under a scanning electron microscopy microscope to assess the interactive mixing behaviour. In addition, the flow performance and tabletting behaviour of various blends were characterised. ResultsThe surface-energy derived work of adhesion (wad) between excipient and paracetamol particles increased, while the corresponding work of cohesion (wco) between excipient particles decreased, with increasing l-leucine concentrations. In blends for which the work of cohesion was higher than the work of adhesion (wco>wad), small excipient particles were apparent as agglomerates. For excipients with 5% and higher l-leucine concentrations, the work of adhesion between excipient and paracetamol particles was higher than or equivalent to the work of cohesion between excipient particles (wad⩾wco) and agglomerates were less apparent. This is an indicator of formation of homogeneous interactive mixtures. At 5% (w/w) excipient proportions, blends for which wad⩾wco demonstrated higher compactibility than other blends. Furthermore, at 10% (w/w) and higher excipient proportions, these blends also demonstrated better flow performance than other blends. ConclusionIn conclusion, this is the first study to demonstrate that surface-energy derived CAB data effectively predict the interactive mixing behaviour of small excipient particles. Furthermore, at certain proportions of small excipient particles the CAB model also predicts the flow and compaction behaviour of the API/excipient blends.

Towards a rational basis for selection of excipients: Excipient Efficiency for controlled release

There are many factors influencing the drug release behaviour from a pharmaceutical formulation as the particle size of the drug and excipient, porosity of the system or geometrical phase transitions of the components. Therefore, the choice of the adequate excipient to achieve a specific drug release profile is mainly based on the experience and the trial and error method. Taking into account the directives towards the application of the “Quality by Design” approach, in this study the Excipient Efficiency (EE), a parameter able to quantify the capability of an excipient to control the drug release, has been developed. EE was initially calculated dividing the total porosity of the system by its diffusional release rate constant. The influence of several factors on this parameter has been evaluated. As a result, the final parameter has been corrected based on the drug solubility and the excipient particle size. EE provides a rational basis for identifying the most adequate excipients for a concrete formulation.

Tablet mechanics depend on nano and micro scale adhesion, lubrication and structure

Tablets are the most convenient form for drug administration. However, despite the ease of manufacturing problems such as powder adhesion occur during the production process. This study presents surface and structural characterization of tablets formulated with commonly used excipients (microcrystalline cellulose (MCC), lactose, mannitol, magnesium (Mg) stearate) pressed under different compaction conditions. Tablet surface analyses were performed with scanning electron microscopy (SEM), profilometry and atomic force microscopy (AFM). The mechanical properties of the tablets were evaluated with a tablet hardness test. Local adhesion detected by AFM decreased when Mg stearate was present in the formulation. Moreover, the tablet strength of plastically deformable excipients such as MCC was significantly decreased after addition of Mg stearate. Combined these facts indicate that Mg stearate affects the particle–particle bonding and thus elastic recovery. The MCC excipient also displayed the highest hardness which is characteristic for a highly cohesive material. This is discussed in the view of the relatively high adhesion found between MCC and a hydrophilic probe at the nanoscale using AFM. In contrast, the tablet strength of brittle materials like lactose and mannitol is unaffected by Mg stearate. Thus fracture occurs within the excipient particles and not at particle boundaries, creating new surfaces not previously exposed to Mg stearate. Such uncoated surfaces may well promote adhesive interactions with tools during manufacture.

Structural changes of polymer-coated microgranules and excipients on tableting investigated by microtomography using synchrotron X-ray radiation

Multiple-unit tablets consisting of polymer-coated microgranules and excipients have a number of advantageous pharmaceutical properties. Polymer-coated microgranules are known to often lose their functionality because of damage to the polymer coating caused by tableting, and the mechanism of polymer coating damage as well as the structural changes of excipients upon tableting had been investigated but without in-situ visualization and quantitative analysis. To elucidate the mechanism of coating damage, the internal structures of multiple-unit tablets were investigated by X-ray computed microtomography using synchrotron X-rays. Cross sectional images of the tablets with sub-micron spatial resolution clearly revealed that void spaces remained around the compressed excipient particles in the tablets containing an excipient composed of cellulose and lactose (Cellactose® 80), whereas much smaller void spaces remained in the tablets containing an excipient made of sorbitol (Parteck® SI 150). The relationships between the void spaces and the physical properties of the tablets such as hardness and disintegration were investigated. Damage to the polymer coating in tablets was found mainly where polymer-coated microgranules were in direct contact with each other in both types of tablets, which could be attributed to the difference in hardness of excipient particles and the core of the polymer-coated microgranules.

Improved blend and tablet properties of fine pharmaceutical powders via dry particle coating

The improvements in the flow and packing of fine pharmaceutical powder blends due to dry coating of micronized acetaminophen (mAPAP, ∼11μm), a model poorly flowing drug, are quantified. Poor flow and packing density of fine excipients (∼20μm) allowed testing the hypothesis that dry coating of cohesive API may counteract poor flow and packing of fine pharmaceutical powder blends. Further, fine excipients could improve compaction and reduce segregation tendency. It was found that flow function coefficient (FFC) and bulk density enhancements for 10%, 30%, and 60% (w/w), API loading blends with dry coated API are significantly higher than those without coated silica. At the highest API loading, for which coarser excipients were also used as reference, the flow and packing of dry coated mAPAP blends were significantly increased regardless of the excipient particle size, exceeding those of a well compacting excipient, Avicel 102. In addition, tensile strength of tablets with fine excipients was significantly higher, indicating improved compactibility. These results show for the first time that dry coating of fine, cohesive API powder leads to significantly improved flow and packing of high API loading blends consisting of fine excipients, while achieving improved tablet compactibility, suggesting suitability for direct compaction.

Application of nano-particle coatings to carrier particles using an integrated fluidized bed supercritical fluid precipitation process

Production of active ingredients such as pharmaceuticals in nano-particulate form is highly desirable but the resulting product is difficult to handle and to use in applications. A novel process is described for coating nanoparticles onto excipient particles of c. 300μm by rapid expansion of a supercritical solution (RESS) into two types of modified proprietary equipment: a Wurster coater and a fluidized bed. This novel approach has been demonstrated through the successful deposition of six mimics for active ingredients (benzoic acid, adamantane, ferrocene, phenanthrene, stearic acid and vitamin K3) on carrier excipient particles of microcrystalline cellulose (MCC). Evidence from SEM, EDX and Confocal Raman microscopy suggests that the coating particles are below 30nm in size. Unlike most conventional coating processes, this approach avoids the use of liquids and high temperatures. As a wide range of actives and excipients can potentially be employed, the approach is applicable across the process and product industries, in particular pharmaceutical, household goods, personal care and catalyst industries.

A Quality-by-Design Study for an Immediate-Release Tablet Platform: Examining the Relative Impact of Active Pharmaceutical Ingredient Properties, Processing Methods, and Excipient Variability on Drug Product Quality Attributes

The impact of filler-lubricant particle size ratio variation (3.4-41.6) on the attributes of an immediate-release tablet was compared with the impacts of the manufacturing method used (direct compression or dry granulation) and drug loading (1%, 5%, and 25%), particle size (D[4,3]: 8-114 μm), and drug type (theophylline or ibuprofen). All batches were successfully manufactured, except for direct compression of 25% drug loading of 8 μm (D[4,3]) drug, which exhibited very poor flow properties. All manufactured tablets possessed adequate quality attributes: tablet weight uniformity <4% RSD, tablet potency: 94%-105%, content uniformity <6% RSD, acceptance value ≤ 15, solid fraction: 0.82-0.86, tensile strength >1 MPa, friability ≤ 0.2% weight loss, and disintegration time < 4 min. The filler-lubricant particle size ratio exhibited the greatest impact on blend and granulation particle size and granulation flow, whereas drug property variation dominated blend flow, ribbon solid fraction, and tablet quality attributes. Although statistically significant effects were observed, the results of this study suggest that the manufacturability and performance of this immediate-release tablet formulation is robust to a broad range of variation in drug properties, both within-grade and extra-grade excipient particle size variations, and the choice of manufacturing method.

New Mechanisms to Explain the Effects of Added Lactose Fines on the Dispersion Performance of Adhesive Mixtures for Inhalation

Fine excipient particles or ‘fines’ have been shown to improve the dispersion performance of carrier-based formulations for dry powder inhalation. Mechanistic formulation studies have focussed mainly on explaining this positive effect. Previous studies have shown that higher drug contents may cause a decrease in dispersion performance, and there is no reason why this should not be true for fines with a similar shape, size and cohesiveness as drug particles. Therefore, the effects on drug detachment of ‘fine lactose fines’ (FLF, X50 = 1.95 µm) with a similar size and shape as micronised budesonide were studied and compared to those of ‘coarse lactose fines’ (CLF, X50 = 3.94 µm). Furthermore, interactions with the inhalation flow rate, the drug content and the mixing order were taken into account. The observed effects of FLF are comparable to drug content effects in that the detached drug fraction was decreased at low drug content and low flow rates but increased at higher flow rates. At high drug content the effects of added FLF were negligible. In contrast, CLF resulted in higher detached drug fractions at all flow rates and drug contents. The results from this study suggest that the effects of fines may be explained by two new mechanisms in addition to those previously proposed. Firstly, fines below a certain size may increase the effectiveness of press-on forces or cause the formation of strongly coherent fine particle networks on the carrier surface containing the drug particles. Secondly, when coarse enough, fines may prevent the formation of, or disrupt such fine particle networks, possibly through a lowering of their tensile strength. It is recommended that future mechanistic studies are based on the recognition that added fines may have any effect on dispersion performance, which is determined by the formulation and dispersion conditions.

Preparation of naproxen–excipient formulations by CO2 precipitation on a slurry

The work focused on screening the impact of various excipients and/or procedure in a new method that consists in a CO2-induced precipitation of a drug on a slurry. Naproxen (NPX) is a drug whose bioavailability could be improved by formulation with hydrophilic excipients. The investigated excipients were of various type, size and porosity, i.e. mannitol, silicas (SiO2 and SIO2 aminopropyl) and an anion exchange resin Duolite. The precipitation process used compressed CO2 as antisolvent for NPX and acetone as solvent to dissolve NPX and to suspend the excipient particles. Naproxen precipitated as crystals with a size distribution influenced by the NPX:excipient ratio for mannitol-based formulations. For other excipient co-precipitates, the overall size distributions were in the same range and below 330μm except for the 5μm silica. Due to the hydrophilic nature of the excipients, most formulations yielded an increased drug dissolution rate. Compared to physical mixtures, the benefit of the CO2 treatment was demonstrated in case of the excipient mannitol.

A Generalized Relation for Solid-State Drug Stability as a Function of Excipient Dilution: Temperature-Independent Behavior

A proposed generalized relationship for the impact of excipients on the solid-state chemical stability of drug products is presented and shown to be consistent across multiple degradation products with two example drugs. In this model, when the number of drug particles is comparable to the number of excipient particles, the impact of the excipient on the degradant formation rate is independent of drug concentration. In contrast, when the number of drug particles is in excess of the number of excipient particles, a power-law relation (linear correlation between the logarithm of the degradant formation rate and the logarithm of the reciprocal of the drug concentration) is proposed based on a "quasi-liquid" model where drug particles fill in interstices between excipients. As predicted by this model, the experimental power-law lines have slopes of about 2/3 independent of temperature (0.61 ± 0.13 for n = 30 counting multiple degradation products and a range of temperatures and relative humidities for two drug products).

Performance of Combination Drug and Hygroscopic Excipient Submicrometer Particles from a Softmist Inhaler in a Characteristic Model of the Airways

Excipient enhanced growth (EEG) of inhaled submicrometer pharmaceutical aerosols is a recently proposed method intended to significantly reduce extrathoracic deposition and improve lung delivery. The objective of this study was to evaluate the size increase of combination drug and hygroscopic excipient particles in a characteristic model of the airways during inhalation using both in vitro experiments and computational fluid dynamic (CFD) simulations. The airway model included a characteristic mouth-throat (MT) and upper tracheobronchial (TB) region through the third bifurcation and was enclosed in a chamber geometry used to simulate the thermodynamic conditions of the lungs. Both in vitro results and CFD simulations were in close agreement and indicated that EEG delivery of combination submicrometer particles could nearly eliminate MT deposition for inhaled pharmaceutical aerosols. Compared with current inhalers, the proposed delivery approach represents a 1-2 order of magnitude reduction in MT deposition. Transient inhalation was found to influence the final size of the aerosol based on changes in residence times and relative humidity values. Aerosol sizes following EEG when exiting the chamber (2.75-4.61μm) for all cases of initial submicrometer combination particles were equivalent to or larger than many conventional pharmaceutical aerosols that frequently have MMADs in the range of 2-3μm.

Assessing powder segregation potential by near infrared (NIR) spectroscopy and correlating segregation tendency to tabletting performance

Segregation is one of the common problems associated with low drug load formulations, particularly for those made by a direct compression process. Segregation of an active pharmaceutical ingredient (API) from excipients can lead to variation in content uniformity, which in turn may result in failure to meet product specification. Segregation not only stems from variation of material properties such as differences of API and excipient particle size, shape and cohesion, but also is highly specific to process handling and specific equipment used. The objective of this study was to examine the effects of particle size and cohesion on the segregation tendency of pharmaceutical powders measured by bench scale sifting and fluidization segregation testers. The test blends consisted of 5% aspirin, 64.5% lactose, 30% microcrystalline cellulose (MCC) and 0.5% magnesium stearate with various aspirin particle size and cohesion value. Aspirin cohesion was varied by coating aspirin particles with Cab-O-Sil M5P. The blends were compressed into tablets by a high speed rotary press using a specially designed hopper, which was intended to simulate segregation tendency at large scale tablet manufacturing. The segregation tendency of the blends was also assessed using bench scale sifting and fluidization segregation testers. Near Infrared (NIR) methods were developed to analyze aspirin content uniformity of blends, segregation samples and tablets. The sifting segregation tester and testing protocol (ASTM D 6940-04) were modified to provide better correlation between the test results and tablet content uniformity. It was found that coating aspirin with Cab-O-Sil M5P can significantly reduce aspirin's cohesion but had little impact on its segregation tendency. The effect of particle size on segregation tendency was quite intriguing. It is commonly believed that large particle size difference between the drug and excipients is a primary factor contributing to segregation. However, our study indicated that one has to consider not only just the particle size difference but also the interaction between aspirin and excipients. Contrary to the common belief, the batch with larger particle size difference had lower segregation potential, which was probably attributed to favorable interaction between aspirin and MCC. In addition to identify the critical physical properties of the blends that influence segregation tendency, the study also highlighted the usefulness of NIR for quantitative analysis as well as the importance of using performance based approach to establish correlation between bench scale powder testing and larger scale manufacturing performance. This graphic abstract depicts key methodologies used in this paper. The aspirin content uniformity was analyzed using the Near Infrared (as shown by the NIR instrument and NIR spectrum). Powder’s segregation tendency was tested with segregation testers (the modified sifting segregation tester is shown), and then correlated to tablet content uniformity (the tablet press with extended hopper and tablet CU over time were shown).

Condensational growth of combination drug-excipient submicrometer particles for targeted high-efficiency pulmonary delivery: evaluation of formulation and delivery device

The objective of this study was to investigate the in-vitro particle-size growth of combination drug and excipient submicrometer aerosols generated from a series of formulations and two aerosol delivery devices. Submicrometer combination drug and excipient particles were generated experimentally using both the capillary aerosol generator and the Respimat inhaler. Budesonide and albuterol sulfate were used as model drugs and were formulated with sodium chloride, citric acid and mannitol as excipients in various ratios. Aerosol growth was evaluated in-vitro in a coiled-tube geometry designed to provide residence times and thermodynamic conditions consistent with the airways. Submicrometer combination drug : excipient aerosols when exposed to simulated respiratory conditions increased to micrometer size suitable for pulmonary deposition. It was possible to control the aerosol growth ratio by altering: (1) the hygroscopic excipient, (2) the drug : excipient ratio and (3) the drug. The applicability of this approach was demonstrated using the capillary aerosol generator and the Respimat inhaler. The enhanced excipient growth approach may enable the delivery of submicrometer aerosol particles that increase in size within the airways and result in high percentages of pulmonary deposition.