Cryo-milled Samples Research Articles

Implications of crystal disorder on the solid-state stability of Olanzapine

Mechanical perturbations of drug during solid pharmaceutical processing like milling can often generate crystal disorder posing serious implications to drug's stability. While physical changes like amorphization, recrystallization, polymorphism of the disordered drugs are extensively studied and reported in the literature, the propensities and inter-dependencies of recrystallization and degradation propensities of disordered drugs have seldom received deep attention. Previous investigations from our lab have explored some of these interplays, aiming to develop predictive stability models. As a follow-up, the implication of crystal disorder on the oxidative instability of Olanzapine (OLA) during accelerated storage is investigated in this work. Cryo-milling OLA at varied time intervals generated different extents of crystal disorder. The milled samples were characterized using calorimetry and infrared (IR) spectroscopy to examine the physical state, while their degradation was evaluated using ultra-performance liquid chromatographic methods. An X-ray amorphous OLA sample was generated by melt-cooling, and used as an amorphous reference. The crystallinity of the cryo-milled samples was quantified using a partial least square regression model based on ATR-FTIR spectroscopic data. The cryo-milled samples were exposed to different accelerated stability conditions along with crystalline (unmilled) and quench cooled (amorphous) samples, serving as controls. At periodic intervals, samples were removed from the stability storage, and analyzed using ATR-FTIR and UPLC methods to quantify the crystallinity- and degradation extents. A positive relation was witnessed between the initial degree of crystallinity and degradation kinetics of the disordered OLA samples during stability storage indicating a strong dependency of degradation on the disorder contents for such disordered solids. The results obtained in this study can potentially explain consequences of inter-batch variations of drugs during stability storage, in addition to enabling de-risking strategies towards eliminating solid drug instabilities in product development.

Breaking Strong Alkynyl-Phenyl Bonds: Poly(para-phenylene ethynylene)s under Mechanical Stress.

Stronger chemical bonds withstand higher mechanical forces; thus, the rupture of single bonds is preferred over the rupture of double or triple bonds or aromatic rings. We investigated bond scission in poly(dialkyl-p-phenylene ethynylene)s (PPEs), a fully conjugated polymer. In a scale-bridging approach using electron-paramagnetic resonance spectroscopy and gel permeation chromatography of cryomilled samples, in combination with density functional theory calculations and coarse-grained simulations, we conclude that mechanical force cleaves the sp-sp2 bond of PPEs (bond dissociation energy as high as 600 kJ mol-1). Bond scission primarily occurs in shear bands with locally increased shear stresses. The scission occurs in the middle of the PPE chains. Breaking sp-sp2 bonds into free radicals thus is feasible but requires significant mechanical force and an efficient stress concentration.

An assessment of methods used for the generation and characterization of cryomilled polystyrene micro- and nanoplastic particles

There is a critical need to generate environmentally relevant microplastics (MPs) and nanoplastics (NPs) to better investigate their behavior in laboratory settings. Environmental MPs are heterogenous in size and shape, unlike monodisperse and uniform microspheres commonly used as surrogates. Cryogenic grinding, or cryomilling, was successfully utilized to transform polystyrene (PS) bulk material into heterogenous micro and nano fragments. Fourier-Transform Infrared (FTIR) spectroscopy confirmed that this approach did not alter polymer surface chemistry. The number of milling cycles (time of milling) and frequency of grinding (intensity of milling) were varied to investigate the role cryomilling parameters had on generated MP characteristics. The resulting particle size distributions of cryomilled samples were measured and compared. Coulter Counter and Nanoparticle Tracking Analysis (NTA) were used to measure the particle size distributions at the micro and nanoparticle size ranges, respectively. Microspheres were used to determine what camera settings yielded more accurate sizing and to reduce bias in the NTA analysis. Increasing milling cycles generally increased the number of smaller particles. The evolution of the measured size distributions indicated that small nanosized fragments broke off from larger MPs during cryomilling, steadily eroding larger MP fragments. The number of milling cycles was observed to more consistently impact the size distributions of fragments compared to the frequency of milling. This study offers both analysis of the cryomilling process and recommendations for generating more realistic PS MP/NPs for examining environmental fate and effects.

Material processing conditions effect on the thermokinetics of end of life tyres

ABSTRACT In this work, end of life tyres (ELTs) samples were subjected to pyrolysis in a dynamic thermogravimetry set-up under various heating rates between 5°C and 25°C min−1. The experimental design involved dried and non-dried sample results in an isothermal step within the heating program, to be able to compare the data against non-dried samples, to further investigate the effect of drying on the results obtained. The drying of the samples resulted in an increase in the onset temperature by some 30°C. However, cryomilling the ELTs samples showed a great effect in reducing the onset of the degradation curve by about 10°C amongst the same set of experiments. The type of sample, in terms of size and processing/milling condition, had a significant impact on the heat flow properties and calorimetry reported. The exothermic region for the original shavings resulted in an enthalpy of −48 J g−1, whilst the cutting mill samples exhibited an enthalpy increase to −184 J g−1. However, the cryomilled samples showed an enthalpy increase estimated at 139 J g−1.

Wear mechanisms maps of CNT reinforced Al6061 nanocomposites treated by cryomilling and mechanical milling

In this study, wear mechanisms of Al6061-CNT nanocomposites produced by cryomilling and mechanical milling, cold compacting and extrusion have been studied. The wear maps showed that the maximum amount of abrasive wear region in all milling times, was observed for the cryomilling samples. Also these maps show that the abrasive wear region for the cryomilling and mechanical milling was maximized at 12h milling time. For cryomilled samples with 8h milling time or more, the weight loss decreases with increasing sliding speed at normal loads of 5 and 10N, also abrasive wear mechanism was observed at above conditions. Cryomilled samples show increased resistance against delamination and crack initiation during wear test.

Nanostructuring of Undoped ZnSb by Cryo-Milling

We report the preparation of nanosized ZnSb powder by cryo-milling. The effect of cryo-milling then hot-pressing of undoped ZnSb was investigated and compared with that of room temperature ball-milling and hot-pressing under different temperature conditions. ZnSb is a semiconductor with favorable thermoelectric properties when doped. We used undoped ZnSb to study the effect of nanostructuring on lattice thermal conductivity, and with little contribution at room temperature from electronic thermal conductivity. Grain growth was observed to occur during hot-pressing, as observed by transmission electron microscopy and x-ray diffraction. The thermal conductivity was lower for cryo-milled samples than for room-temperature ball-milled samples. The thermal conductivity also depended on hot-pressing conditions. The thermal conductivity could be varied by a factor of two by adjusting the process conditions and could be less than a third that of single-crystal ZnSb.

The Effect of Grain Size on the Cyclic Oxidation of NiCoCrAlY

NiCoCrAlY samples were fabricated via spark-plasma sintering with and without prior cryomilling of the as-received powder. Thermal cycling oxidation tests were conducted at 1000°C in air for up to 200 1-h cycles. The mass gain data indicate a notably lower mass gain for the cryomilled NiCoCrAlY sample. In both the conventional and cryomilled samples, scanning electron microscopy and x-ray diffraction data indicate a single-layer oxide scale of α-alumina has formed, having undergone a transition from θ-alumina during oxidation testing. Spallation in the conventional sample allowed a significant amount of internal spinel oxide formation, and this was not found in the cryomilled sample. The difference in behavior is attributed to increased pathways for aluminum diffusion to the surface and nucleation sites for the α-alumina transition, as well as improved scale adhesion through nanostructuring and stress relief through the accelerated θ–α transition.

The effect of grain size on the oxidation of NiCoCrAlY

Ultrafine NiCoCrAlY samples have been obtained through cryomilling of NiCoCrAlY feedstock powder and sintering via SPS, these samples have been subjected to isothermal oxidation tests at 950, 1000 and 1050°C. Oxidation rates on the order of 10−13g2/cm4/s for samples oxidized at 950°C, 10−11g2/cm4/s at 1000°C and 10−12g2/cm4/s at 1050°C have been found. In all cases cryomilled samples demonstrate lower overall oxidation rates than their conventional counterparts. Lower overall oxidation rates found in the cryomilled samples are ascribed to an earlier transition trough the metastable alumina phases, resulting in a stable slow growing α-Al2O3. Characterization by XRD and SEM corresponds well with this assessment. Lower oxidation rates seen at 1050 than at 1000°C in both conventional and cryomilled samples is the result of a change from oxidation dominated by θ-alumina to oxidation dominated by α-alumina, as the θ–α transition speeds up with increasing temperature. This change in oxidation regime reduces, but does not eliminate, the beneficial impact of smaller grain size on oxidation rate.

Structure and morphology of composites based on polyvinylidene fluoride filled with BaTiO3submicrometer particles: Effect of processing and filler content

Composites based on polyvinylidene fluoride filled with barium titanate (PVDF/BT) submicrometric particles were prepared. To uniformly disperse BT particles within PVDF, high-energy ball cryomilling was used. The effect of processing and the presence of BT particles on the structure and morphology of the composites were analyzed by Fourier transformed infrared spectroscopy, X-ray diffraction, differential scanning calorimetry, and atomic force microscopy. In terms of the structure, it can be concluded/stated that after milling the α- and γ-PVDF crystalline phases are reduced, whereas the content in the β phase is increased. On the other hand, after film formation, the α phase was recovered. It was demonstrated that the milling process is the most important factor to increase the amount of β phase, being favored by the presence of BT particles. In terms of the morphology, it was observed that the PVDF lamellar aspect ratio increases with the amount of BT in cryomilled samples processed as films. Besides, the crystallization kinetics is highly affected by the milling process and the presence of BT, being the relative crystallization rate slower with the presence of BT. POLYM. COMPOS., 34:2094–2104, 2013. © 2013 Society of Plastics Engineers

Effect of different preparation methods on the dissolution behaviour of amorphous indomethacin

The aim of this study was to investigate whether amorphous indomethacin samples prepared using different preparative techniques and processing parameters exhibit different structural and thermodynamic characteristics and whether these differences can be correlated to their dissolution behaviour. Samples were prepared either by cooling the drug melt at different cooling rates or by cryo-milling the drug for different milling times. The resulting amorphous materials were characterised using X-ray diffraction, Raman spectroscopy and polarising light microscopy. All samples were entirely X-ray amorphous, except for the sample cryo-milled for 15min, which exhibited residual crystallinity. The shape of the halos in the diffractograms, however, varied depending on the preparation method and processing parameters, suggesting structural variations in the near order of the molecules between the prepared amorphous forms. This finding was supported by principal component analysis of the Raman spectra, as the samples clustered in the scores plot according to processing parameters for both of the preparative methods used. When investigating the dissolution behaviour, the samples cooled at different cooling rates showed no significant differences in their dissolution profiles and dissolution rates (≈0.55μg/ml/cm2). In contrast, for cryo-milled samples, dissolution rate depended on the milling time, with samples milled for 120, 180 and 240min, showing significantly increased dissolution rates of 0.28, 0.48 and 0.59μg/ml/cm2, respectively, when compared to crystalline indomethacin (≈0.06 and 0.05μg/ml/cm2 for α and γ-indomethacin, respectively). The milling processes appear to continue to affect the degree of disorder in the solid material, enhancing its dissolution rate, although all samples milled for >30min were X-ray amorphous. Thus, choosing the right preparation technique and parameters for preparing amorphous solids is critical for producing materials with enhanced dissolution profiles.

Assessment of crystalline disorder in cryo-milled samples of indomethacin using atomic pair-wise distribution functions

The aim of this study was to investigate the usefulness of the atomic pair-wise distribution function (PDF) to detect the extension of disorder/amorphousness induced into a crystalline drug using a cryo-milling technique, and to determine the optimal milling times to achieve amorphisation. The PDF analysis was performed on samples of indomethacin obtained by cryogenic ball milling (cryo-milling) for different periods of time. X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), polarised light microscopy (PLM) and solid state nuclear magnetic resonances (ss-NMR) were also used to analyse the cryo-milled samples. The high similarity between the γ-indomethacin cryogenic ball milled samples and the crude γ-indomethacin indicated that milled samples retained residual order of the γ-form. The PDF analysis encompassed the capability of achieving a correlation with the physical properties determined from DSC, ss-NMR and stability experiments. Multivariate data analysis (MVDA) was used to visualize the differences in the PDF and XRPD data. The MVDA approach revealed that PDF is more efficient in assessing the introduced degree of disorder in γ-indomethacin after cryo-milling than MVDA of the corresponding XRPD diffractograms. The PDF analysis was able to determine the optimal cryo-milling time that facilitated the highest degree of disorder in the samples. Therefore, it is concluded that the PDF technique may be used as a complementary tool to other solid state methods and that further investigations are warranted to elucidate the capabilities of this technique.

Effect of cryo-milling on starches: Functionality and digestibility

Four commercial starches, potato starch (PS), maize starch (MS), and two high amylose maize starches (HAMS), were cryo-milled, with and without hydration, for 20 min to study the effect of milling on physicochemical properties and enzyme digestibility. There was a significant increase in cold water soluble and damaged starch in cryo-milled samples in the order PS > MS > HAMS. Viscosity parameters of milled starches were significantly lower than for native starches, although changes in pasting temperature were not significant. In vitro digestion of native starches showed that enzyme resistance followed the order PS > HAMS > MS. A significant increase in enzyme digestion rate was observed after cryo-milling PS and HAMS but not MS. However, cryo-milled PS and HAMS were still less rapidly-digested than native MS. Scanning electron microscopy (SEM) of native, milled and digested starches showed a uniform ‘inside-out’ digestion pattern for MS, whereas a heterogeneous and nonspecific pattern was observed for PS and HAMS. This study suggests that milling has predominantly mechanical rather than thermal effects on starches and that the relative enzyme resistance of PS and HAMS granules compared with MS is due to the absence of the structural features of MS granules that allow internal access of enzymes.

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 °C for the 30 min cryo-milled sample and around 75 °C for the 60 min 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.

The nature of crystal disorder in milled pharmaceutical materials

The purpose of this study was to study the nature of disorder in milled crystalline materials. Specifically to elucidate if the induced disorder represents crystal defects or amorphous regions. Felodipine and griseofulvin were chosen as model drugs and subjected to milling. Cryomilling was chosen in order to mitigate the influence of heat generated by the process. Amorphous drug samples were produced by quenching the melt. Crystalline, amorphous and cryomilled drug samples were characterized by powder X-ray diffraction (PXRD), thermal analysis (DSC), thermal polarization (thermally stimulated polarization current), and surface energy (inverse gas chromatography). The PXRD analysis shows that cryomilling reduces the crystallinity of the two drugs, while maintaining the same crystal form. Heat capacity measurements (DSC) show that milled material for either drug does not exhibit a glass transition but shows instead an exothermic (crystallization like) event. The thermal polarization profiles revealed that none of the modes of molecular motion (polarization peaks) characteristic of the amorphous form were observed in either the unmilled crystalline or milled forms for either drug. For each drug, the polarization spectra of milled forms were similar, but not identical, to those of the corresponding unmilled crystalline materials. Inverse gas chromatography (IGC) measurements showed that the surface energy of cryomilled samples was higher than those of the unmilled and amorphous forms for both drugs. The polarization and heat capacity measurements show that the disorder induced by milling either griseofulvin or folodipine consists of crystal defects rather than amorphous regions. The exothermic event in the milled samples is attributed to the crystallization of defects in the crystal. These results when combined with the IGC measurements indicate that the milled material retains its crystalline character, making it more stable (at the core) than the amorphous form. However, the milled material has also the most active surface, making it the more interactive with other surfaces as an activated powder.

Physicochemical Properties and Stability of Two Differently Prepared Amorphous Forms of Simvastatin

The purpose of this work was to investigate possible differences in physicochemical properties and stability between amorphous forms of simvastatin prepared by (a) cryo-milling and (b) melting and quench-cooling. Both methods resulted in X-ray amorphous forms and HPLC analysis indicated a small percentage of chemical degradation during the preparation processes. Modulated differential scanning calorimetry (MTDSC) results showed significantly different onset temperatures of recrystallization and recrystallization enthalpies for both amorphous forms. Raman spectra of the amorphous forms showed differences in the intensities of the methylene bands for the cryo-milled and quench-cooled forms. Upon storage at 20 °C, the cryo-milled samples recrystallized within one day, whereas the quench-cooled samples showed no signs of recrystallization, even when stored at 40 °C for 3 days. Principal component analysis was carried out to further analyze any differences in the Raman spectra. The results indicate the existence of an amorphous form for the cryo-milled simvastatin that is spectrally distinguishable from the quench-cooled amorphous form. The thermodynamic parameters suggest that this form is less disordered compared to the quench-cooled form.