Self-reported preclinical mobility limitation and fall history as predictors of future falls in older women: prospective cohort study

Summary  

We studied if self-reported preclinical mobility limitation, described as modification of task performance without perception of difficulty, predicts future falls in older women with and without fall history. Our results suggest that combined measure of self-reported preclinical mobility limitation and fall history may offer one possibility for inexpensive fall-risk evaluation in clinical practice.     

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.     

Polymer-Mediated Anti-solvent Crystallization of Nitrendipine: Monodispersed Spherical Crystals and Growth Mechanism

Purpose  

To investigate anti-solvent crystallization and growth mechanism of nitrendipine spherical crystals in an aqueous solution containing polymeric additives.     

Solvent-mediated amorphous-to-crystalline transformation of nitrendipine in amorphous particle suspensions containing polymers

The amorphous-to-crystalline transformation of nitrendipine was investigated using Raman spectroscopy and X-ray powder diffraction (XRPD). The nucleation and growth rate of crystalline nitrendipine in a medium containing poly (vinyl alcohol) (PVA) and polyethylene glycol (PEG 200) were quantitatively determined using image analysis based on polarized light microscopy. The findings from the image analysis revealed that the transformation process occurred through the dissolution of amorphous drug precipitate followed by the nucleation and growth of the crystalline phase with the amorphous precipitate acting as a reservoir for maintaining the supersaturation. The rates of nucleation and crystal growth of nitrendipine decreased with an increase in PEG 200 concentration in organic phase from 0% to 75% (v/v). Increasing the PVA concentration in water phase from 0.1% to 1.0% (w/w) also decreased the rates of nucleation and crystal growth, however, an increase in PVA concentration from 1.0% to 2.0% (w/w) did not result in a further decrease in the rates of nucleation and crystal growth. An increase in drug concentrations in the organic phase from 10 mg/ml to 30 mg/ml led to faster nucleation rates. However, a further increase in drug concentration to 100mg/ml decelerated the growth of nitrendipine crystals. Combining image analysis of polarized light micrographs together with Raman spectroscopy and XRPD provided an in-depth insight into solid state transformations in amorphous nitrendipine suspensions.     

Behaviour of HPMC compacts investigated using UV-imaging

The aim of the study was to visualize the behaviour of the hydroxypropyl methylcellulose (HPMC) in a buffer solution using UV imaging. The obtained results were related to rheological measurements in order to gain insight into critical polymer properties affecting drug release. Two viscosity grades of HPMC, 15cP and 50 cP, were used. The behaviour of the polymer at the surface of the compact was observed by UV-imaging at 214 nm for 90 min in a stagnant buffer solution and in presence of flow. Steady shear and oscillatory shear measurements were conducted to determine the rheological characteristics. Three distinctive phases could be detected by real-time UV-imaging of the HPMC; gel formation due to water penetration, further expansion of the gel into solution and finally steady conditions, where a critical polymer concentration that can withstand the shear forces without eroding was observed. The critical concentration corresponded to the rheologically determined gel point, which is the lowest concentration where a 3D-network is obtained. Higher viscosity grade HPMC swelled more rapidly and lead to a thicker gel layer, which was more resistant towards the shear forces due to the applied flow. The results showed that UV imaging is suitable for obtaining both qualitative and quantitative information on polymer behaviour.     

A novel image analysis methodology for online monitoring of nucleation and crystal growth during solid state phase transformations

This study focuses on the development of an automated image analysis method to extract information on nucleation and crystal growth from polarized light micrographs. Using the developed image analysis method, four parameters related to nucleation and crystal growth could be extracted from the images. These parameters were crystalline count (applied as a measure of nucleation), percentage area coverage, average equivalent diameter and average crystalline area (three last parameters applied as a measure for crystal growth). The developed image analysis method was used to investigate two pharmaceutically relevant case studies: first, nitrendipine antisolvent crystallization, and second, recrystallization of amorphous piroxicam solid dispersion in an aqueous environment. In both case studies, an amorphous-to-crystalline phase transformation were observed, which were successfully monitored using real-time Raman spectroscopy. For the both case studies, the parameters related to crystallization kinetics estimated by image analysis were in close agreement with the parameters estimated by Raman spectroscopy. The developed image analysis method proved to be a valuable tool for quantitative monitoring of nucleation and crystal growth with an obvious potential for high throughput screening.     

Increasing process understanding by analyzing complex interactions in experimental data

There is a recognized need for new approaches to understand unit operations with pharmaceutical relevance. A method for analyzing complex interactions in experimental data is introduced. Higher-order interactions do exist between process parameters, which complicate the interpretation of experimental results. In this study, experiments based on mixed factorial design of coating process were performed. Drug release was analyzed by traditional analysis of variance (ANOVA) and generalized multiplicative ANOVA (GEMANOVA). GEMANOVA modeling is introduced in this study as a new tool for increased understanding of a coating process. It was possible to model the response, that is, the amount of drug released, using both mentioned techniques. However, the ANOVA model was difficult to interpret as several interactions between process parameters existed. In contrast to ANOVA, GEMANOVA is especially suited for modeling complex interactions and making easily understandable models of these. GEMANOVA modeling allowed a simple visualization of the entire experimental space. Furthermore, information was obtained on how relative changes in the settings of process parameters influence the film quality and thereby drug release.     

Fall-related injuries among initially 75- and 80-year old people during a 10-year follow-up

The aim of this study was to investigate the occurrence, type, scene and seasonal variation of fall related injuries, and the impact of socio-economic factors, mobility limitation, and the most common diseases on the risk of injurious falls over a 10-year follow-up. Elderly residents of Jyv?skyl?, Finland, aged initially 75 and 80 years, took part in the study in 1989-1990. The health and functional capacity assessments were carried out at the baseline. Injurious falls were monitored over a 10-year period. The rate of injurious falls per thousand person-years was 188 among women and 78 among men. Of all fall-related diagnoses, head injuries comprised 32%, upper limb injuries 27% and hip injuries 19%. Majority of injurious falls took place indoors and no seasonal variation in fall occurrence was observed. Recurring falls were more likely to take place in institutions. Osteoarthritis increased the risk of injurious falls but no effect was observed for coronary heart diseases or mobility limitation. All in all, intrinsic factors, such as chronic diseases and mobility limitation had only minor effect on risk of injurious falls among older people. The current results suggest that preventive interventions for injurious falls among older people should pay attention to the risk factors present indoors.