Effect of Roughness on the Dispersion of Dry Powders for Inhalation: a Dynamic Visualization Perspective.

Dry powder inhalers have attracted more interest over the years in every aspect related to them. Interestingly, when focusing on the effects of particle morphology of the active or carrier (excipient), it is generally regarded particle size and shape to influence drug availability of aerosolized particles. However, to date, few studies have examined the effect of texture, i.e., roughness, on this relationship. The main objective of the present work is to gain a closer understanding of the influence of carrier morphology on the aerosolization performance of dry powder inhaler formulations. Image analysis and microscopy were used to visualize the aerosolization process. It is considered that the scale of morphological features on the surface of the carrier particles is responsible for the dispersion of the powder formulation, separation of the drug/carrier, and entrainment from a dry powder inhaler. Thus, for this study, the carrier particles of different surface roughness were mixed with micronized salbutamol sulphate. Aerosolization in vitro testing was used to evaluate the performance. The results indicate a connection between the qualitative surface roughness of coarse carriers and aerosolization performance during powder dispersibility. This investigation demonstrated that indeed, powder dispersion, a dynamic process, is influenced by the scale of the carrier morphology.

Effect of pH and Ionic Strength on the Solubility of Quinoline: Back-to-Basics.

The interest of quinoline as a contaminant agent and as scaffold for the development of new therapeutic agent warrants to revisit the pH-solubility behavior of quinoline (Q) and quinoline derivatives (Q-derivatives) with possible salting-out effect. Q is a weak base with potential hazard upon exposure that may be occupational by inhalation or ingestion of or dermal exposure to particulates in certain industries; or simply by inhalation of cigarette smoke. In contrast, quinoline and its derivatives are useful in diverse therapeutic applications such as anticancer, antiseptic, antipyretic, antiviral, and antimalarial. These claims have raised the possibility of using quinoline motif for the synthesis of new drugs; however, it may act as a pollutant on soil and water as ionizable organic compounds (IOC). The solubility and partitioning behavior of Q may be a critical factor in determining the extent of inhalation and oral absorption or sorption onto soil and water. Studies on the solubility of Q have been reported; however, due to Q-derivatives distinctive usage, it is necessary to revisit and evaluate the solubility profile of Q at different pH levels and ionic strengths. This study reports a simple analytical method for determining the solubility of nitrogen heterocyclic compounds and possible salting-out effect as a function of pH, buffer concentration, and ionic strength. This information can be of value when developing Q-derivatives and to enhance understanding of Q as well as its derivatives behavior in the gastrointestinal tract or when evaluating the presence of Q as an environmental contaminant.

Powder dispersion mechanisms within a dry powder inhaler using microscale particle image velocimetry.

The goal of this work was to evaluate the ability of Particle Image Velocimetry (PIV) to visually assess dry powder dispersion within an inhaler. Herein, the study reports particle movement characterization of entrained low-micron particles within an inhaler to further scheme of potential mechanisms. Carrier based DPI formulations were prepared and placed in a transparent model Rotahaler® chamber for the aerosolization experiments. Then using the PIV, a high-speed camera, the dried powder dispersion was directly observed and analyzed for all, neat, binary and ternary systems. Powder dispersion mechanisms proposed include drag force, impact with obstacle and particle-particle collision; these different mechanisms depended on the powder flow properties. A revised ratio of aerodynamic response time (τA) to the mean time between collisions (τC) was found to be 6.8 indicating that particle collisions were of strong influence to particle dispersion. With image analysis techniques, visualization of particle flow pattern and collision regions was possible; suggesting that the various mechanisms proposed did govern the powder dispersion.

Stain removal effect of novel papain- and bromelain-containing gels applied to enamel.

OBJECTIVES: The aims of the study are to prepare novel stain removal gel-based formulations containing papain or bromelain and to investigate their stain removal effect when applied to enamel. MATERIALS AND METHODS: Experimental bromelain- and papain-based stain removal gels were prepared. Next, enamel/dentin tooth samples (6 × 6 mm2, 4 mm in thickness) were obtained from bovine teeth, stained in coffee solution for 1 week, and measured with a digital spectrophotometer (Easyshade, Vita Zahnfabrik) for color assessment (baseline). The samples were then randomly allocated into four groups (n = 7), according to the stain removal agent applied: ContrastPM+ (Discus Dental, LLC), which is based on 20 wt.% carbamide peroxide (positive control); bromelain-based; papain-based; and no agent (negative control). The materials were applied once a week, three times per day, during 4 weeks, and following the directions of use from positive control. The samples were measured again with the Easyshade and using the CIEL * a * b * color system. The color change (ΔE *) results were obtained by subtracting the baseline values from the final color values obtained at each time point. The data were statistically analyzed using two-way repeated-measures analysis of variance and Student Newman Keuls's test as a post hoc test (α = 5 %). RESULTS: All stain removal agents produced greater color change than the negative control (p < .001), with the positive control demonstrating greater ΔE * values when compared to the experimental gels (p ≤ .004). The second application of all gels resulted in greater ΔE * values compared to the first application (p ≤ .025), although no color change was observed after the third application (p ≥ .051), regardless of the material evaluated. CLINICAL SIGNIFICANCE: The proposed gels containing proteolytic enzymes (bromelain or papain) of vegetal origin may hold significant clinical potential as active agents for the preparation of stain removal agents free of hydrogen/carbamide peroxide.

Nanomechanical testing technique for millimeter-sized and smaller molecular crystals.

Large crystals are used as a control for the development of a mounting and nanoindentation testing technique for millimeter-sized and smaller molecular crystals. Indentation techniques causing either only elastic or elastic-plastic deformation produce similar results in assessing elastic modulus, however, the elastic indents are susceptible to surface angle and roughness effects necessitating larger sample sizes for similar confidence bounds. Elastic-plastic indentations give the most accurate results and could be used to determine the different elastic constants for anisotropic materials by indenting different crystal faces, but not by rotating the indenter about its axis and indenting the same face in a different location. The hardness of small and large crystals is similar, suggesting that defect content probed in this study is similar, and that small crystals can be compared directly to larger ones. The Young's modulus and hardness of the model test material, griseofulvin, are given for the first time to be 11.5GPa and 0.4GPa respectively.

The influence of API concentration on the roller compaction process: modeling and prediction of the post compacted ribbon, granule and tablet properties using multivariate data analysis.

OBJECTIVE: While previous research has demonstrated roller compaction operating parameters strongly influence the properties of the final product, a greater emphasis might be placed on the raw material attributes of the formulation. There were two main objectives to this study. First, to assess the effects of different process variables on the properties of the obtained ribbons and downstream granules produced from the rolled compacted ribbons. Second, was to establish if models obtained with formulations of one active pharmaceutical ingredient (API) could predict the properties of similar formulations in terms of the excipients used, but with a different API. MATERIALS AND METHODS: Tolmetin and acetaminophen, chosen for their different compaction properties, were roller compacted on Fitzpatrick roller compactor using the same formulation. Models created using tolmetin and tested using acetaminophen. The physical properties of the blends, ribbon, granule and tablet were characterized. Multivariate analysis using partial least squares was used to analyze all data. RESULTS: Multivariate models showed that the operating parameters and raw material attributes were essential in the prediction of ribbon porosity and post-milled particle size. The post compacted ribbon and granule attributes also significantly contributed to the prediction of the tablet tensile strength. CONCLUSIONS: Models derived using tolmetin could reasonably predict the ribbon porosity of a second API. After further processing, the post-milled ribbon and granules properties, rather than the physical attributes of the formulation were needed to predict downstream tablet properties. An understanding of the percolation threshold of the formulation significantly improved the predictive ability of the models.

Thermal insight of mechanically activated bile acid powders.

Mechanical activation of pharmaceutical materials presents an important but poorly understood phenomenon of milled molecular crystals. In this work, a strategy was followed in an effort to understand this phenomenon, cryo-milled of both crystalline and amorphous counterpart of bile acids materials were characterized by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). The XRPD results for the 30-min milled crystalline powders displayed a characteristic amorphous halo patterns for all compounds tested. The DSC thermograms exhibited the typical glass transition temperatures (T(g)) associated with amorphous but only for two materials. For the remaining four milled compounds, a rather interesting behavior was manifested through a characteristic exothermal bimodal peak. The findings seemed to suggest that the occurrence of this event was not related to the (T(g)), but likely to the melting temperature (T(m)). The DSC results for the melt-quenched (amorphous) ursodeoxycholic acid after cryo-milling revealed that the material crystallized after the influence of the mechanical stress, and a bimodal peak was also observed similar to that of the cryo-milled crystalline material. It is contemplated that the response of the physical instability of the disordered phase could be explained either by the result of surface crystallization kinetics which is different from that of the bulk crystallization, or by the creation of supersaturated dislocated crystal prior to amorphization.

Determination of the scale of segregation of low dose tablets using hyperspectral imaging.

In this work, near infrared (NIR) hyperspectral imaging was used to quantify the spatial distribution of drug in tablets containing tolmetin sodium dihydrate. Hyperspectral data cubes were generated by imaging the same spatial region of a sample while illuminated by a laser at a different wavelength for each image. Images were generated for wavelengths ranging from 1100 to 2200 nm. Ten tablets with concentrations ranging from 0.0 to 10.0% w/w tolmetin were imaged, and the scales of segregation were calculated for the tablets. Lactose anhydrous was used as the diluent, and all mixtures contained 0.5% magnesium stearate as a lubricant. This research has shown hyperspectral imaging to be viable tool for quantifying segregation of low dose drugs in tablets.

Assessment of milling-induced disorder of two pharmaceutical compounds.

The goal of this study was to provide a better framework for understanding the bulk and surface disorder in milled crystalline materials. The surface and bulk properties of two model compounds, ketoconazole and griseofulvin, were characterized by inverse gas chromatography as a function of cryomilling time. Cryomilling was used to decrease the effect of temperature-induced changes, which commonly occur during milling. A reduction in crystallinity was observed for both compounds by powder X-ray diffraction and differential scanning calorimetry (DSC). Particle size analysis revealed a continued mode of attrition for griseofulvin, whereas attrition followed by growth was observed for ketoconazole. An increase in surface energy for both compounds was noticed upon initial milling, followed by a decrease as milling time continued. A determination and comparison of the surface phase transformations using chromatographic methods and DSC was carried out. Both ketoconazole and griseofulvin showed an earlier phase transformation relative to DSC. It is proposed that an intermediate metastable state for griseofulvin and a change in the surface structure of ketoconazole is the consequence of the cryomilling process.

Improvement of the dissolution rate of poorly soluble drugs by solid crystal suspensions.

We present a novel extrusion based approach where the dissolution rate of poorly soluble drugs (griseofulvin, phenytoin and spironolactone) is significantly accelerated. The drug and highly soluble mannitol are coprocessed in a hot melt extrusion operation. The obtained product is an intimate mixture of the crystalline drug and crystalline excipient, with up to 50% (w/w) drug load. The in vitro drug release from the obtained solid crystalline suspensions is over 2 orders of magnitude faster than that of the pure drug. Since the resulting product is crystalline, the accelerated dissolution rate does not bear the physical stability concerns inherent to amorphous formulations. This approach is useful in situations where the drug is not a good glass former or in cases where it is difficult to stabilize the amorphous drug. Being thermodynamically stable, the dissolution profile and the solid state properties of the product are maintained after storage at 40 °C, 75% RH for at least 90 days.

Vibrational imaging of tablets by epi-detected stimulated Raman scattering microscopy.

Proper chemical imaging tools are critical to the pharmaceutical industry due to growing regulatory demand for intermediate and end-product content uniformity testing. Herein we demonstrate stimulated Raman scattering (SRS) imaging of active pharmaceutical ingredient (API) and four excipients within tablets. Tablets from six manufactures were imaged with a speed of 53 s per frame of 512 × 512 pixels (i.e., 200 µs per pixel) and a lateral spatial resolution as high as 0.62 µm. The SRS chemical imaging was compared to confocal Raman mapping and coherent anti-Stokes Raman scattering (CARS) chemical imaging in terms of speed and chemical selectivity. The acquisition speed of SRS imaging is ca. 10(4) times faster than confocal Raman mapping and SRS technique showed superior to CARS chemical selectivity for studied samples. Our data demonstrate the potential of SRS microscopy in high-speed screening of pharmaceutical solid dosage forms.

A novel method to measure the glass and melting transitions of pharmaceutical powders.

A method to measure thermo-mechanical properties of pharmaceutical and polymeric powders was developed. The measurements are conducted by characterizing the material's response to applied acoustic waves. Measurements were performed using griseofulvin, felodipine and indomethacin as model drugs and polyethylene oxide (MW=200,000, 900,000, 2,000,000Da) as model polymers. The method employed measures the mechanical impedance enabled the calculation of the powder rheological and thermo-mechanical properties. Measurements attained with this new technique are compared with measurements made using differential scanning calorimetry (DSC) and dynamic mechanical analysis (DMA). The new method detects the melting and glass transitions events while providing complementary information to that provided by DSC and DMA.

The effect of dehydration conditions on the functionality of anhydrous amorphous raffinose.

The purpose of this investigation is to study the effect of dehydration conditions of raffinose pentahydrate (RF.5H2O) on the physical properties and functionality of the resulting material. Crystalline RF.5H2O was dehydrated at two temperatures, 80 degrees C and 110 degrees C, producing the amorphous anhydrous form (RF.am). The dehydration temperature had no effect on a number of physical properties of the obtained RF.am, including X-ray powder diffraction, surface energy and water uptake. However, despite resulting on the same dynamics and extent of water sorption, different dehydration temperatures produced amorphous samples with drastically different recrystallization tendencies. Thermodynamic parameters show that despite the similarities on certain physical attributes, different dehydration temperature results in samples with significantly different free energy, hence stability. The difference in free energy produced by the dehydration temperature is attributed to differences in supramolecular structure that persist even in the liquid domain (above T(g)) of the amorphous samples. Evidence of such effects is observed as fluctuations in heat capacity present in RF.am but absent in the freshly prepared glass and also supported by the presence of molecular mobility modes observed using thermal polarization measurements.

Assessment of Thermal Transitions by Dynamic Mechanical Analysis (DMA) Using a Novel Disposable Powder Holder.

Foods and pharmaceuticals materials are exposed to various environmental conditions during processing and while in storage; therefore, stability and quality are key attributes of concern. The properties of foods and pharmaceutical materials that define their quality are affected by conditions such as temperature, humidity and time. Glass transition is considered a key material property to understand how these external conditions affect the stability and quality of foods and pharmaceuticals. Thus, investigating the thermo-mechanical properties of these materials as well as characterizing the glass transition temperature have a great interest not only in the food industry, but also extend to the pharmaceutical and polymer industries. The aim of this study was to design and test a new disposable powder holder that allows the use of a dynamic mechanical analysis (DMA) instrument to test and characterize loose powder samples. The disposable aluminum powder holder was designed and constructed to be used in the single cantilever configuration on a TA Instruments RSA III DMA. Three different powder samples - Felodipine, polyethylene-oxide (MW 900 kDa) and HPMC (E4M) - were used for validation. The use of this powder holder allows the detection of different thermal changes of powder samples without compacting and when large sample size is necessary for detection and/or interpretation.

Elucidating raw material variability--importance of surface properties and functionality in pharmaceutical powders.

The purpose of this study is to illustrate, with a controlled example, the influence of raw material variability on the excipient's functionality during processing. Soluble starch was used as model raw material to investigate the effect of variability on its compaction properties. Soluble starch used in pharmaceutical applications has undergone a purification procedure including washing steps. In this study, a lot of commercially available starch was divided into two parts. One was left intact and the other was subjected to an extra washing step. The two resulting lots were subjected to a series of physical characterization tests typical of those used to qualify raw materials. The two resulting lots gave virtually identical results from the tests. From the physical testing point of view, the two lots can be considered as two equivalent lots of the same excipient. However, when tested for their functionality when subjected to a compaction process, the two lots were found to be completely different. The compaction properties of the two lots were distinctly different under all environmental and processing conditions tested. From the functionality point of view, the two lots are two very different materials. The similar physical testing results but different functionality can be reconciled by considering the surface properties of the powders. It was found that the washing step significantly altered the surface energetic properties of the excipient. The washed lot consistently produced stronger compacts. These results are attributable to the measurably higher surface energy of induced by the additional washing step.

Interactions between bovine serum albumin and alginate: an evaluation of alginate as protein carrier.

The intermolecular interactions between the model protein, bovine serum albumin (BSA) and a biocompatible polysaccharide, sodium alginate, have been investigated. Both the native BSA and the heat pre-denatured BSA were utilized to study, in parallel, the effect of protein conformational change during the protein-alginate complex formation. In this work, a comparison was performed between the native BSA and the heat-denatured BSA incubated sodium alginate mixtures by using zeta potential analyzer, dynamic light scattering (DLS) and turbidimetric analysis of the systems in combination with protein conformational tools, Fourier transform infrared spectroscopy (FT-IR) and size exclusion chromatography (SE-HPLC). The experimental results demonstrate that the intermolecular chain associations were formed between alginate chains and protein molecules in either the native form or the heat pre-denatured form, mainly driven by the electrostatic interactions between the oppositely charged amino acids and the anionic polysaccharide macromolecules. However, the majority of BSA was recovered from the dissociation of protein-alginate complexes and maintained its secondary structure and conformational property. Therefore, alginate is promising as a bioactive compound carrier.

Toward understanding the evolution of griseofulvin crystal structure to a mesophase after cryogenic milling.

The purpose of this research is to investigate the response of crystalline griseofulvin to mechanically induced stress through cryogenic milling. Crystalline griseofulvin was subjected to cryogenic milling for two different lengths of time. Following cryo-milling, the samples were immediately analyzed by differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). The DSC thermograms of cryo-milled griseofulvin showed a complex exothermic event at around 65 degrees C for the 30min cryo-milled sample and around 75 degrees C for the 60min cryo-milled sample. A glass transition event was not observed for the cryo-milled samples. This is in direct contrast to the X-ray amorphous griseofulvin sample prepared through the quench melt method The XRPD patterns of cryo-milled griseofulvin show a loss of the crystalline Bragg peaks and a corresponding increase in diffuse scattering (halos). The disordered griseofulvin material produced through cryo-milling appears X-ray amorphous, yet different from the amorphous phase produced using the quench melt method. Both X-ray amorphous materials have distinctive DSC thermograms and X-ray powder patterns. These findings suggest that the evolution of the griseofulvin crystal structure during cryo-milling is not simply a crystal-to-amorphous transition but a transition to an intermediate mesophase.

Utility of multivariate analysis in modeling the effects of raw material properties and operating parameters on granule and ribbon properties prepared in roller compaction.

This article aimed to model the effects of raw material properties and roller compactor operating parameters (OPs) on the properties of roller compacted ribbons and granules with the aid of principal component analysis (PCA) and partial least squares (PLS) projection. A database of raw material properties was established through extensive physical and mechanical characterization of several microcrystalline cellulose (MCC) and lactose grades and their blends. A design of experiment (DoE) was used for ribbon production. PLS models constructed with only OP-modeled roller compaction (RC) responded poorly. Inclusion of raw material properties markedly improved the goodness of fit (R(2) = .897) and model predictability (Q(2) = 0.72).

Investigation of the variability of NIR in-line monitoring of roller compaction process by using Fast Fourier Transform (FFT) analysis.

The purpose of this research was to investigate the variability of the roller compaction process while monitoring in-line with near-infrared (NIR) spectroscopy. In this paper, a pragmatic method in determining this variability of in-line NIR monitoring roller compaction process was developed and the variability limits were established. Fast Fourier Transform (FFT) analysis was used to study the source of the systematic fluctuations of the NIR spectra. An off-line variability analysis method was developed as well to simulate the in-line monitoring process in order to determine the variability limits of the roller compaction process. For this study, a binary formulation was prepared composed of acetaminophen and microcrystalline cellulose. Different roller compaction parameters such as roll speed and feeding rates were investigated to understand the variability of the process. The best-fit line slope of NIR spectra exhibited frequency dependence only on the roll speed regardless of the feeding rates. The eccentricity of the rolling motion of rollers was identified as the major source of variability and correlated with the fluctuations of the slopes of NIR spectra. The off-line static and dynamic analyses of the compacts defined two different variability of the roller compaction; the variability limits were established. These findings were proved critical in the optimization of the experimental setup of the roller compaction process by minimizing the variability of NIR in-line monitoring.

Process induced disorder in crystalline materials: differentiating defective crystals from the amorphous form of griseofulvin.

This research investigates milling induced disorder in crystalline griseofulvin. Griseofulvin was subjected to cryogenic milling for various lengths of time. For comparison, the amorphous form of griseofulvin was also prepared by the quench melt method. Different analytical techniques were used to study the differences between the cryomilled, amorphous and crystalline forms of the drug. Cryogenic milling of griseofulvin progressively reduces the crystallinity of the drug by inducing crystal defects, rather than amorphous materials. Raman analysis provides evidence of structural differences between the two. The differences between the defective crystals produced by milling and the amorphous form are significant enough as to be measurable in their bulk thermal properties. Defective crystals show significant decrease in the heat of fusion as a function of milling time but do not exhibit a glass transition nor recrystallization from the amorphous form. Crystal defects undergo recrystallization upon heating at temperatures well below the glass transition temperature (T(g)) in a process that is separate and completely independent from the crystallization of the amorphous griseofulvin, observed above T(g). Physical mixtures of defective crystals and amorphous drug demonstrate that the thermal events associated with each form persist in the mixtures, unaffected by the presence of the other form.