Robustness of a continuous direct compression line against disturbances in feeding.

The aim of the current study was to characterize the robustness of an integrated continuous direct compression (CDC) line against disturbances from feeding, i.e. impulses of API and short step disturbances. These disturbances mimicked typical variations that can be encountered during long-term manufacture. The study included a primary formulation, with API of standard particle size, which was manufactured at 5 and 10 kg/h production rates, and a modified formulation, with API of large particle size, which was manufactured at 5 kg/h production rate. Overall, the CDC line smoothened all the disturbances, fulfilling the USP uniformity of dosage units (UDU) limit for single tablets. However, runs with the modified formulation failed the pharmacopoeia UDU requirements for the entire run due to high variation between tablets. The primary formulation passed the requirements in all cases. The residence time distribution (RTD) results indicated that the primary formulation allowed better smoothening ability, and an increase in production rate led to poorer smoothening due to shorter RTD. The RTDs revealed that a substantial part of back-mixing took place after the blender. Thus, the tablet press has an important role in smoothening disturbances longer than the mean residence time of the blender, which was very short.

RTD-based material tracking in a fully-continuous dry granulation tableting line.

Continuous manufacturing (CM) offers quality and cost-effectiveness benefits over currently dominating batch processing. One challenge that needs to be addressed when implementing CM is traceability of materials through the process, which is needed for the batch/lot definition and control strategy. In this work the residence time distributions (RTD) of single unit operations (blender, roller compactor and tablet press) of a continuous dry granulation tableting line were captured with NIR based methods at selected mass flow rates to create training data. RTD models for continuous operated unit operations and the entire line were developed based on transfer functions. For semi-continuously operated bucket conveyor and pneumatic transport an assumption based the operation frequency was used. For validation of the parametrized process model, a pre-defined API step change and its propagation through the manufacturing line was computed and compared to multi-scale experimental runs conducted with the fully assembled continuous operated manufacturing line. This novel approach showed a very good prediction power at the selected mass flow rates for a complete continuous dry granulation line. Furthermore, it shows and proves the capabilities of process simulation as a tool to support development and control of pharmaceutical manufacturing processes.

Complexation with tolbutamide modifies the physicochemical and tableting properties of hydroxypropyl-beta-cyclodextrin.

The physicochemical and tableting properties of hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and its tolbutamide (TBM) complex were studied. The kinetics of TBM/HP-beta-CD inclusion complex formation in solution were determined by the phase solubility method. Solid complexes were prepared by freeze-drying and spray-drying. Water sorption-desorption behaviour of the materials were studied and compacts were made using a compaction simulator. TBM and HP-beta-CD formed 1:1 inclusion complexes in aqueous solution with an apparent stability constant of 63 M(-1). HP-beta-CDs and TBM/HP-beta-CD complexes were amorphous whereas the freeze-dried and spray-dried TBMs were polymorphic forms II and I, respectively. Sorption-desorption studies showed that HP-beta-CDs were deliquescent at high relative humidities. TBM/HP-beta-CD complexes had slightly lower water contents at low relative humidities than the physical mixtures. However, at high humidities their water sorption and desorption behaviours were similar to those of corresponding physical mixtures, indicating a glass transition of the complexed materials. TBM/HP-beta-CD complexes demonstrated a worse compactability than similarly prepared HP-beta-CDs or physical mixtures. Also particle properties that resulted from these preparation methods affected the compactability of the materials. In conclusion, the physicochemical and tableting properties of HP-beta-CD were modified by complexation it with TBM.

Deformation behaviors of tolbutamide, hydroxypropyl-beta-cyclodextrin, and their dispersions.

PURPOSE: The deformation behaviors of compressed freeze-dried and spray-dried tolbutamide/hydroxypropyl-beta-cyclodextrin molecular dispersions were evaluated and compared with similarly prepared tolbutamides (TBM), hydroxypropyl-beta-cyclodextrins (HP-beta-CD) and as their physical dispersions. METHODS: TBM, HP-beta-CD, and their 1:1 molecular dispersions were prepared by freeze-drying and spray-drying, and physical dispersions of TBM and HP-beta-CD were blended. Deformation properties of the prepared materials were evaluated by using a compaction simulator and constants derived from Heckel plots. Molecular dynamics (MD) simulations were performed in order to gain a molecular-level view on the deformation behavior of TBM-HP-beta-CD inclusion complex. RESULTS: The freeze-dried TBM polymorphic form II was less prone to overall particle deformation than the spray-dried stable form I. Formation of molecular dispersions decreased the plastic and elastic behaviors of these materials. Also, the MD simulations showed a reduced molecular flexibility of the TBM-HP-beta-CD inclusion complex, as compared to HP-beta-CD. CONCLUSIONS: The formation of TBM and HP-beta-CD molecular dispersion resulted in more rigid molecular arrangements, which were less prone to deformation than either HP-beta-CDs or physical dispersions. The results showed how differing molecular, solid, particle, and powder state properties affect the deformation properties of the materials studied.

Cardiorespiratory responses to fatiguing dynamic and isometric hand-grip exercise.

In occupational work, continuous repetitive and isometric actions performed with the upper extremity primarily cause local muscle strain and musculoskeletal disorders. They may also have some adverse effects on the cardiorespiratory system, particularly, through the elevation of blood pressure. The aim of the present study was to compare peak cardiorespiratory responses to fatiguing dynamic and isometric hand-grip exercise. The subjects were 21 untrained healthy men aged 24-45 years. The dynamic hand-grip exercise (DHGE) was performed using the left hand-grip muscles at the 57 (SD 4)% level of each individual's maximal voluntary contraction (MVC) with a frequency of 51 (SD 4) grips x min(-1). The isometric hand-grip exercise (IHGE) was done using the right hand at 46 (SD 3)% of the MVC. The endurance time, ventilatory gas exchange, heart rate (HR) and blood pressure were measured during both kinds of exercise. The mean endurance times for DHGE and IHGE were different, 170 (SD 62) and 99 (SD 27) s, respectively (P < 0.001). During DHGE the mean peak values of the breathing frequency [20 (SD 6) breaths x min(-1)] and tidal volume [0.89 (SD 0.34) l] differed significantly (P < 0.01) from peak values obtained during IHGE [15 (SD 5) breaths x min(-1) and 1.14 (SD 0.32) l, respectively]. The corresponding peak oxygen consumptions, pulmonary ventilations, HR and systolic blood pressures did not differ, and were 0.51 (SD 0.06) and 0.46 (SD 0.11) l x min(-1), 17.1 (SD 3.0) and 16.7 (SD 4.7) l x min(-1), 103 (SD 18) and 102 (SD 17) beats x min(-1), and 156 (SD 17) and 161 (SD 17) mmHg, respectively. The endurance times of both DHGE and IHGE were short (< 240 s). The results indicate that the peak responses for the ventilatory gas exchange, HR and blood pressure were similar during fatiguing DHGE and IHGE, whereas the breathing patterns differed significantly between the two types of exercise. The present findings emphasize the importance of following ergonomic design principles in occupational settings which aim to reduce the output of force, particularly in tasks requiring isometric and/or one-sided repetitive muscle actions.

Physical activity, fitness and body composition of Finnish police officers: a 15-year follow-up study.

This study evaluated changes in the physical activity, fitness and body composition of 103 police officers during a 15-year follow-up. The absolute aerobic capacity was similar in 1981 and 1996, muscular performance had declined, and body weight had increased approximately 0.5 kg/year. More than half the subjects (53%) had increased their leisure-time physical activity in 1996. The correlation was significant between physical activity in 1981 and physical fitness in 1996, but weak between physical activity in 1996 and fitness in 1996. It was also significant between waist circumference and waist/hip ratio in 1996 and physical activity during the previous 5 and 15 years. No significant correlations were found between physical activity and work ability or perceived physical or mental job stress. The physical fitness of middle-aged police officers seems to be predicted strongly by physical activity in early adulthood. Therefore health and fitness promotion measures should start at that time. This, together with regular systematic training, should help to sustain work ability of middle-aged police officers.

Physiological strain during kitchen work in relation to maximal and task-specific peak values.

Six female and three male subjects from a hospital kitchen volunteered for the study. The subjects were working on a conveyor belt collecting and sorting dirty plates, glasses and cutlery for cleaning. In the study, a medical examination, a maximal clinical exercise test with a 12-lead electrocardiogram (ECG) and a maximal arm cranking test were performed in the laboratory. Further, each subject was studied for 30 min during a normal work shift in the kitchen. Oxygen uptake (VO2) and heart rate (HR) were continuously registered. During the work period, a rating of perceived exertion (RPE) was asked at the 5th, 15th and 30th minute. Physiological responses were measured by a portable system (K4) both in the laboratory and in the field. VO2 and HR measured in the field were proportioned to corresponding maximal values during cycling and to peak values during arm-cranking. The mean VO2 for the male and the female subjects during kitchen work was 0.65 +/- 0.16 l min-1. This corresponded to 24% of VO2max and to 41% of VO2peak during arm-cranking. The difference was significant (p < 0.001). Owing to a magnetic field at the conveyor belt, reliable HR values were obtained only from the female subjects. The mean HR during work among the female subjects was 101 beats min-1. It corresponded to 55% of HRmax and 67% of HRpeak during arm-cranking (p < 0.05). The present study shows that the relative work intensity is markedly higher when it is expressed relative to the corresponding muscle group's VO2peak instead of the VO2max. Similar difference was also seen in the HR response. More task-specific testing of physical capacity may provide improved evaluation of physical strain in a job.

Heart rate and blood pressure responses to isometric exercise in young and older men.

The aim of this study was to examine the isometric endurance response and the heart rate and blood pressure responses to isometric exercise in two muscle groups in ten young (age 23-29 years) and seven older (age 54-59 years) physically active men with similar estimated forearm and thigh muscle masses. Isometric contractions were held until fatigue using the finger flexor muscles (handgrip) and with the quadriceps muscle (one-legged knee extension) at 20%, 40%, and 60% of the maximal voluntary contraction (MVC). Heart rate and arterial pressure were related to the the individual's contraction times. The isometric endurance response was longer with handgrip than with one-legged knee extension, but no significant difference was observed between the age groups. The isometric endurance response averaged 542 (SEM 57), 153 (SEM 14), and 59 (SEM 5) s for the handgrip, and 276 (SEM 35), 94 (SEM 10) and 48 (SEM 5) s for the knee extension at the three MVC levels, respectively. Heart rate and blood pressure became higher during one-legged knee extension than during handgrip, and with increasing level of contraction. The older subjects had a lower heart rate and a higher blood pressure response than their younger counterparts, and the differences were more apparent at a higher force level. The results would indicate that increasing age is associated with an altered heart rate and blood pressure response to isometric exercise although it does not affect isometric endurance.

Prediction of acceptable physical work loads based on responses to prolonged arm and leg exercise.

Nine healthy men (aged 54-59 years) performed arm crank and leg cycle exercises for 30 min at relative work loads of 50 and 75% of peak oxygen uptake (VO2) for the corresponding muscle group, and for 60 min at a relative work load of 30% of peak VO2 for the corresponding muscle group. In the tests, heart rate (HR), blood pressure, gas exchange variables, rating of perceived exertion (RPE) and blood lactate were measured. At the 75% target exercise level, four subjects interrupted the arm-cranking test, and one subject interrupted the leg-cycle test. Owing to differences in peak values during arm-cranking and leg-cycling, the work load and the VO2 were higher during leg-cycling than during arm-cranking. There was no difference in HR between the work modes, but the HR increased to a greater extent during arm-cranking compared to leg-cycling at the 30% (NS) and 50% (P < 0.05) exercise levels. Similarly, the RPE increased more during arm-cranking compared to leg-cycling at each exercise level. The blood lactate concentration was higher after arm-cranking than after leg-cycling; at the 50% exercise level the difference was statistically significant. The results indicate a higher physiological strain with time during arm exercise than during leg exercise at the same muscle group-specific relative work load. The acceptable physical work load, expressed as the percentage peak VO2 for the corresponding muscle group, should thus be lower during arm exercise than during leg exercise. The RPE and the relative HR, expressed as percentage of peak HR for the corresponding muscle group, however, seem to be comparable indicators for the physiological strain during arm and leg exercise.

Cardiorespiratory and subjective responses to prolonged arm and leg exercise in healthy young and older men.

Ten young (aged 23-30 years) and nine older (aged 54-59 years) healthy men with a similar size of limb muscle mass performed arm crank and leg cycle exercise for 30 min at relative exercise intensities of 50% and 75% of maximal oxygen uptake for the corresponding muscle group. In the tests, heart rate, blood pressure, gas exchange variables, rating of perceived exertion and blood lactate concentration were measured. The limb muscle mass was determined by anthropometric measurements. At the 75% target exercise level, four of the older men and two of the young men could not complete the arm-cranking test, and one of the older men and two of the young men could not complete the leg-cycle test. During arm-cranking the absolute exercise intensity was similar for the young and older men because of similar maximal values during arm-cranking. But during leg-cycling the absolute exercise intensity was higher for the young men than for the older men due to the difference in corresponding maximal values. During arm-cranking there were no significant differences in the physiological responses between the age groups except that a higher ventilatory response was noted among the older compared to the young men. During leg-cycling the heart rate values were higher among the young compared to the older men. But, when the heart rate values were expressed as a percentage of maximal heart rate in the corresponding maximal tests, no significant differences between the age groups were found. The results indicated that 30-min of arm or leg exercise at the same relative submaximal exercise intensity produces a similar degree of physiological strain in healthy older compared to young men. During armcranking, the young and the older men exercised at the same external intensity, indicating a similar ability to perform prolonged excercise using smaller muscle groups expressed both in absolute and relative terms.

A thirteen-year follow-up of respiratory effects of acute exposure to sulfur dioxide.

OBJECTIVES: In 1977, nine men were accidentally exposed to sulfur dioxide in an explosion in a pyrite mine. The lung function of seven men was followed after the accident. A four-year follow-up has been published previously. The greatest decrease in forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1.0), and maximal midexpiratory flow (MMEF) was observed one week after the accident, after which all these parameters improved without reaching the preaccident level. Reversible bronchial obstruction was still present in three patients, and a positive reaction in the histamine challenge test was found for four. In the present paper, the lung function follow-up 13 years after the accident is reported for six men. METHODS: The patients' clinical condition, chest X-ray, spirometry, and histamine challenge test were studied 13 years after the incident. RESULTS: Spirometry was normal in one worker, two displayed obstruction, and three had a combined obstructive and restrictive, mainly obstructive, ventilatory impairment. In the histamine challenge test, four patients showed bronchial hyperreactivity, one with a nearly significant reaction. Because of bronchial obstruction one patient could not perform the challenge test. CONCLUSIONS: This 13-year follow-up showed that acute inflammatory obstruction caused by exposure to sulfur dioxide left, as sequelae, obstructive impairment of ventilatory function and permanent bronchial hyperreactivity. The clinical picture displayed by these patients was named the "reactive airways dysfunction syndrome" (RADS) in 1985. Four of the patients also showed symptoms of chronic bronchitis.

Physical work capacity in dynamic exercise with differing muscle masses in healthy young and older men.

Ten young (aged 23-30 years) and nine older (aged 54-59 years) healthy men with similar estimated limb muscle volumes performed, in random order, three different types of ergometer exercise tests (one-arm cranking, two-arm cranking, and two-leg cycling) up to the maximal level. Values for work load (WL), peak oxygen consumption (V0(2)), peak heart rate (HR), peak ventilation (V(E)), respiratory gas exchange ratio (R), recovery blood lactate concentration [La-], and rating of perceived exertion (RPE) were compared between the age-groups in the given exercise modes. No significant age-related differences in WL, peak V0(2), peak HR, R, [La-], or RPE were found in one-arm or two-arm cranking. During one-arm cranking the mean peak V0(2) was 1.65 (SD 0.26)1*min(-1) among the young men and 1.63 (SD 0.10)l*min(-1) among the older men. Corresponding mean peak V0(2) during two-arm cranking was 2.19 (SD 0.32)1*min(-1) and 2.09 (SD 0.18)1*min(-1), respectively. During one-arm cranking peak V(E) was higher (P <0.05) among the older men compared to the young men. During two-leg cycling the young men showed higher values in WL (P <0.001), peak V0(2) (P <0.001), and peak HR (P <0.001). The mean peak V0(2) was 3.54 (SD 0.24)1*min(-1) among the young men and 3.02 (SD 0.20)1 . min(-1) among the older men. Corresponding mean peak HR was 182 (SD 5) beats*min(-1) and 170 (SD 8) beats*min(-1), respectively. During two-leg cycling, peak V(E), R, [La-], and RPE did not differ between the two age-groups. In summary, the older men with similar sizes of estimated arm and leg muscle volumes as the young men had a reduced physical work capacity in two-leg cycling. In one-arm or two-arm cranking, no significant difference in work capacity was found between the age-groups. These results indicate, that in healthy men, age, at least up to the 6th decade of life, is not necessarily associated with a decline in physical work capacity in exercises using relatively small muscle groups, in which the limiting factors are more peripheral than central.

Physiological responses of firefighting students during simulated smoke-diving in the heat.

While wearing a self-contained breathing apparatus and fire-protective clothing, 35 healthy firefighting students aged 19-27 years performed smoke-diving (entry into a smoke-filled room) during a simulated shipboard fire. The mean (+/- SD) ambient temperature inside the simulator was 119 +/- 12 degrees C, and the task lasted 17 +/- 4 min. All subjects were fit according to their maximal oxygen consumption, which was 52.4 +/- 5.2 mL/min/kg (4.08 +/- 0.45 l/min). During the smoke-diving the average heart rate was 150 +/- 13 beats/min (79 +/- 6% of maximal heart rate attained in a cycle-ergometer test), and the peak heart rate was 180 +/- 13 beats/min (95 +/- 6% of maximal heart rate). The estimated oxygen consumption was 2.4 +/- 0.5 L/min (60 +/- 12% of maximal oxygen consumption). Neither ability to tolerate stress (as determined by the instructors) nor previous experience in smoke-diving tasks seemed to influence the heart rate or estimated oxygen consumption during experiment. Smoke-diving was physically very demanding even for the young and fit subjects, showing the importance of regular evaluation of the health and physical fitness of every firefighter who has to carry out smoke-diving tasks.

Thermoregulation during rest and exercise in the cold in pre- and early pubescent boys and in young men.

Eight minimally dressed pre- and early pubescent boys (age 11-12 yr) and 11 young adult men (age 19-34 yr) rested for 20 min and exercised on a cycle ergometer for 40 min at approximately 30% of their maximum oxygen consumption (VO2max) at 5 degrees C. To quantify the added increase in metabolic rate because of cold, a separate test was carried out at 21 degrees C at rest and at equal work rates as in the cold. Both groups were similar in subcutaneous fat thickness and VO2max per kilogram body weight. Rectal temperature increased slightly during the exposure to the cold, but no significant difference was observed between the boys and men. In the cold, the boys had lower skin temperatures than the adults in their extremities but not in the trunk. The boys increased their metabolic rates in the cold more than did the men. As a result, the boys maintained their core temperature as effectively as the adults. Similar age-related differences in thermoregulatory responses to cold were observed when two boys and two men with equal body sizes were compared. Our results suggest that there may be maturation-related differences in thermoregulation in the cold between children and adults.

Biomechanical evaluation of heavy tool-handling in two age groups of firemen.

The biomechanical load of a rescue-clearing task (lifting a power saw from the floor up to the ceiling level) was evaluated with six older (47 +/- 5 years) and seven younger firemen (32 +/- 2 years). The mean dynamic compressive force at the L5/SI disc was 5998 N for the older subjects and 6392 N for the younger subjects. The peak torques for the back and knee extensions were about equal for the two groups of the subjects. The younger subjects had a significantly higher movement speed in the knee extension than the older subjects (89.1 +/- 25.7 vs. 35.3 +/- 11.5 degrees/s, p less than 0.001). The results showed that lifting a power saw produced a high load on the musculoskeletal system, and that the load was not influenced by age.

Effect of work load on cutaneous vascular response to exercise.

The purpose of the present study was to examine whether intensity of exercise affects skin blood flow response to exercise. For this purpose, six healthy men cycled, in a random order on different days, for 15 min at 50, 60, 70, 80, and 90% of their maximum oxygen consumption (VO2max) at a room temperature of 25 degrees C. At the end of exercise, esophageal temperature (Tes) averaged 37.4 +/- 0.2, 37.7 +/- 0.2, 37.9 +/- 0.2, 38.6 +/- 0.3, and 38.9 +/- 0.4 degrees C (SE) at the 50, 60, 70, 80, and 90% work loads, respectively. At the two highest work loads, no steady state was observed in Tes. Skin blood flow was estimated by measuring forearm blood flow (FBF) with strain-gauge plethysmography and by laser-Doppler flowmetry on the upper back. Both techniques showed that skin blood flow response to rising Tes was markedly reduced at the 90% work load compared with other work loads. At the end of exercise, FBF averaged 7.5 +/- 1.7, 10.7 +/- 3.1, 9.6 +/- 2.1, 11.3 +/- 2.6, and 5.4 +/- 1.3 (SE) ml.min-1.100 ml-1 (P less than 0.01) at the 50, 60, 70, 80, and 90% VO2max work loads, respectively. The corresponding values for Tes threshold for cutaneous vasodilation (FBF) were 37.42 +/- 0.16, 37.48 +/- 0.13, 37.59 +/- 0.13, 37.79 +/- 0.19, and 38.20 +/- 0.22 degrees C (P less than 0.05) at 50, 60, 70, 80, and 90% VO2max, respectively. In two subjects, no cutaneous vasodilation was observed at the 90% work load.(ABSTRACT TRUNCATED AT 250 WORDS)

Aerobic capacity among chronic low-back-pain patients.

The role of aerobic capacity (maximal oxygen uptake, VO2max) in connection with chronic low-back pain was assessed in a study mainly designed to evaluate the outcome of inpatient and outpatient treatment of low-back pain. A total of 245 subjects (ages 35-54 years, 71% men)--81 inpatients, 88 outpatients, and 76 controls--who had chronic low-back pain but who were still working, performed maximal graded bicycle ergometer tests four times during the follow-up of 30 months. In every group the estimated VO2max was on the level of the reference values of healthy persons. There were no significant changes in the VO2max in any of the intervention groups during the follow-up period. The correlation analyses showed no connection between aerobic capacity and pain or disability caused by chronic low-back pain. Among several components of physical fitness, aerobic capacity had no predictive value in the course of low-back pain.

An evaluation of heat stress indices (ISO 7243, ISO/DIS 7933) in the prediction of heat strain in unacclimated men.

The ISO 7243 heat stress standard based on the wet bulb globe temperature (WBGT) heat stress index and the analytical standard proposal ISO/DIS 7933 were evaluated in eight physically trained and eight untrained, unacclimated men during prolonged light exercise carried out while wearing industrial work clothing. The exercise tests were done in a thermoneutral (20 degrees C/40%), a warm humid (30 degrees C/80% humidity), and a hot dry (40 degrees C/20% humidity) environment. Both of the standards were effective in predicting the excessive thermal strain observed in the dry and humid heat (WBGT, 28 degrees C). In dry heat, neither of the standards took into account the higher sweating capacities of the physically trained men. The large inter-individual variability in the physiological responses to heat stress questioned the calculations of definite allowable exposure times (ISO/DIS 7933).

Changes in maximal cardiorespiratory capacity among aging municipal employees.

Before and after a four-year follow-up, maximal oxygen consumption (VO2max) was determined for 67 municipal employees (initial age about 51 years). The VO2max (ml.kg-1) decreased 6% among the women and increased 8% among the men, the greatest and smallest change occurring for employees doing mental and physical work, respectively. The men's increase was associated with an increase in leisure-time physical activity. Work content was not associated with the level of VO2max for either gender. After the four years the women's absolute VO2max was about 66% of the men's. There were marked changes in VO2max at the individual level, the most marked decreases being associated with the use of medication in some cases. After the four years the women's VO2max of 63% was insufficient according to current recommendations. Therefore physically demanding jobs are not generally recommended for older women.