Molecular Dynamics and Physical Stability of Amorphous Nimesulide Drug and Its Binary Drug-Polymer Systems.

In this article we study the effectiveness of three well-known polymers: inulin, Soluplus, and PVP in stabilizing the amorphous form of nimesulide (NMS) drug. The recrystallization tendency of pure drug as well as measured drug-polymer systems were examined at isothermal conditions by broadband dielectric spectroscopy (BDS) and at nonisothermal conditions by differential scanning calorimetry (DSC). Our investigation has shown that the crystallization half-life time of pure NMS at 328 K is equal to 33 min. We found that this time can be prolonged to 40 years after adding 20% w/w PVP to NMS. This polymer proved to be the best NMS stabilizer, while the worst stabilization effect was exhibited by inulin. Additionally, our DSC, BDS, and FTIR studies indicate that for suppression of NMS recrystallization in the NMS-PVP system, the two mechanisms are responsible: the polymeric steric hindrances and the antiplastization effect exerted by the excipient.

Stabilization of the Amorphous Ezetimibe Drug by Confining Its Dimension.

The purpose of this paper is to investigate the influence of nanoconfinement on the molecular mobility, as well as on the physical stability, of amorphous ezetimibe drug. Two guest/host systems, ezetimibe-Aeroperl 300 and ezetimibe-Neusilin US2, were prepared and studied using various experimental techniques, such as X-ray diffraction (XRD), differential scanning calorimetry (DSC), and broadband dielectric spectroscopy (BDS). Our investigation has shown that the molecular mobility of the examined anticholesterol agent incorporated into nanopore matrices strongly depends on the pore size of the host system. Moreover, it was found that the amorphous ezetimibe confined in 30 nm pores of Aeroperl 300 has a tendency to recrystallize, while the drug incorporated into the smaller--5 nm--pores of Neusilin US2 is not able to crystallize. It has been shown that this significant stabilization of ezetimibe drug can be achieved by an interplay of three factors: changes in molecular dynamics of the confined amorphous drug, the immobilization effect of pore walls on a part of ezetimibe molecules, and the use of host materials with pores that are smaller than the critical size of the drug crystal nuclei.

Amorphous Protic Ionic Systems as Promising Active Pharmaceutical Ingredients: The Case of the Sumatriptan Succinate Drug.

In this article, we highlight the benefits coming from the application of amorphous protic ionic systems as active pharmaceutical ingredients (APIs). Using the case of the sumatriptan (STR) drug, we show that the conversion of nonionic API to partially ionized amorphous protic succinate salt (STR SUCC) brings a substantial improvement in apparent solubility. Since in general the disordered systems reveal a tendency to self-arrangement during storage, the dominant part of this article is dedicated to the physical stability issue of sumatriptan and its ionic counterpart. To recognize the crystallization tendency of the studied systems, the calorimetric measurements were performed. Additionally, the role of ion dynamics in spontaneous nucleation of amorphous sumatriptan succinate is discussed. The differential scanning calorimetry analysis of ionic and nonionic sumatriptan reveals many similarities in thermal properties of these APIs as well as distinct differences in their resistance against crystallization in the supercooled liquid state. To determine the long-term physical stability of STR SUCC at room temperature conditions, the time scale of structural relaxation below their glass transition temperatures is estimated. We show that in contrast to nonionic materials, τα predictions of STR SUCC are much more complex and require aging experiments.

Universal Behavior of Dielectric Responses of Glass Formers: Role of Dipole-Dipole Interactions.

From an exhaustive examination of the molecular dynamics in practically all van der Waals molecular glass formers ever probed by dielectric spectroscopy, we found that the width of the α-loss peak at or near the glass transition temperature T_{g} is strongly anticorrelated with the polarity of the molecule. The larger the dielectric relaxation strength Δε(T_{g}) of the system, the narrower is the α-loss peak. This remarkable property is explained by the contribution from the dipole-dipole interaction potential V_{dd}(r)=-Dr^{-6} to the attractive part of the intermolecular potential, making the resultant potential more harmonic, and the effect increases rapidly with the dipole moment µ and Δε(T_{g}) in view of the relation, D∝(µ^{4}/kT_{g})∝kT_{g}[Δε(T_{g})]^{2}. Since the novel correlation discovered encompasses practically all van der Waals molecular glass formers studied by dielectric spectroscopy, it impacts the large dielectric research community as well as those engaged in solving the glass transition problem.

Ionic liquids and their bases: Striking differences in the dynamic heterogeneity near the glass transition.

Ionic liquids (ILs) constitute an active field of research due to their important applications. A challenge for these investigations is to explore properties of ILs near the glass transition temperature Tg, which still require our better understanding. To shed a new light on the issues, we measured ILs and their base counterparts using the temperature modulated calorimetry. We performed a comparative analysis of the dynamic heterogeneity at Tg for bases and their salts with a simple monoatomic anion (Cl(-)). Each pair of ionic and non-ionic liquids is characterized by nearly the same chemical structure but their intermolecular interactions are completely different. We found that the size of the dynamic heterogeneity of ILs near Tg is considerably smaller than that established for their dipolar counterparts. Further results obtained for several other ILs near Tg additionally strengthen the conclusion about the relatively small size of the dynamic heterogeneity of molecular systems dominated by electrostatic interactions. Our finding opens up new perspectives on designing different material properties depending on intermolecular interaction types.

Toward a Better Understanding of the Physical Stability of Amorphous Anti-Inflammatory Agents: The Roles of Molecular Mobility and Molecular Interaction Patterns.

The aim of this article is to examine the crystallization tendencies of three chemically related amorphous anti-inflammatory agents, etoricoxib, celecoxib, and rofecoxib. Since the molecular mobility is considered as one of the factors affecting the crystallization behavior of a given material, broadband dielectric spectroscopy was used to gain insight into the molecular dynamics of the selected active pharmaceutical ingredients. Interestingly, our experiments did not reveal any significant differences in their relaxation behavior either in the supercooled liquid or in the glassy state. Hence, as a possible explanation for the enhanced physical stability of etoricoxib, its ability to undergo a tautomerization reaction was recognized. The occurrence of intramolecular proton transfer in the disordered etoricoxib was proven experimentally by time-dependent dielectric and infrared (IR) measurements. Additionally, IR spectroscopy combined with density functional theory calculations pointed out that in the etoricoxib drug, being in fact a binary mixture of tautomers, the individual isomers may interact with each other through a hydrogen bonding network. A possible explanation of this issue was achieved by performing dielectric experiments at elevated pressure. Since compression results in etoricoxib recrystallization, the possible influence of pressure on the observed stabilization effect is also carefully discussed.

Dynamic Properties of Glass-Formers Governed by the Frequency Dispersion of the Structural α-Relaxation: Examples from Prilocaine.

General and fundamental properties of glass-formers of various chemical bonding and physical structures have been found in the recent past. These important findings should be key to gain basic understanding of the dynamics at all time scales leading to glass transition. However, the entirety of these general properties has not been found in a single glass-former. For others to appreciate the importance of these properties, they need to collect the supporting experimental data from different glass-formers scattered over many publications. This hurdle may account for the current lack of universal recognition of the importance of these general properties by the research community. In this paper we present experimental studies of the dynamic processes over a broad range of time scales of a single glass-former, prilocaine. Practically the entire collection of fundamental properties has been found in this system. The advance should heighten the awareness of the importance of these properties in anyone's effort to solve the glass transition problem.

Molecular Dynamics and Physical Stability of Coamorphous Ezetimib and Indapamide Mixtures.

Low physical stability is the main reason limiting the widespread use of amorphous pharmaceuticals. One approach to overcome this problem is to mix these drugs with various excipients. In this study coamorphous drug-drug compositions of different molar ratios of ezetimib and indapamid (i.e., EZB 10:1 IDP, EZB 5:1 IDP, EZB 2:1 IDP, EZB 1:1 IDP and EZB 1:2 IDP) were prepared and investigated using differential scanning calorimetry (DSC), broadband dielectric spectroscopy (BDS), and X-ray diffraction (XRD). Our studies have shown that the easily recrystallizing ezetimib drug can be significantly stabilized in its amorphous form by using even a small amount of indapamid (8.8 wt %). DSC experiments indicate that the glass transition temperature (Tg) of the tested mixtures changes with the drug concentration in accordance with the Gordon-Taylor equation. We also investigated the effect of indapamid on the molecular dynamics of the ezetimib. As a result it was found that, with increasing indapamid content, the molecular mobility of the binary drug-drug system is slowed down. Finally, using the XRD technique we examined the long-term physical stability of the investigated binary systems stored at room temperature. These measurements prove that low-molecular-weight compounds are able to significantly improve the physical stability of amorphous APIs.

Physicochemical properties of tadalafil solid dispersions - Impact of polymer on the apparent solubility and dissolution rate of tadalafil.

To improve solubility of tadalafil (Td), a poorly soluble drug substance (3µg/ml) belonging to the II class of the Biopharmaceutical Classification System, its six different solid dispersions (1:1, w/w) in the following polymers: HPMC, MC, PVP, PVP-VA, Kollicoat IR and Soluplus were successfully produced by freeze-drying. Scanning electron microscopy showed a morphological structure of solid dispersions typical of lyophilisates. Apparent solubility and intrinsic dissolution rate studies revealed the greatest, a 16-fold, increase in drug solubility (50µg/ml) and a significant, 20-fold, dissolution rate enhancement for the Td/PVP-VA solid dispersion in comparison with crystalline Td. However, the longest duration of the supersaturation state in water (27µg/ml) over 24h was observed for the Td solid dispersion in HPMC. The improved dissolution of Td from Td/PVP-VA was confirmed in the standard dissolution test of capsules filled with solid dispersions. Powder X-ray diffraction and thermal analysis showed the amorphous nature of these binary systems and indicated the existence of dispersion at the molecular level and its supersaturated character, respectively. Nevertheless, as evidenced by film casting, the greatest ability to dissolve Td in polymer was determined for PVP-VA. The crystallization tendency of Td dispersed in Kollicoat IR could be explained by the low Tg (113°C) of the solid dispersion and the highest difference in Hansen solubility parameters (6.8MPa(0.5)) between Td and the polymer, although this relationship was not satisfied for the partially crystalline dispersion in PVP. Similarly, no correlation was found between the strength of hydrogen bonds investigated using infrared spectroscopy and the physical stability of solid dispersions or the level of supersaturation in aqueous solution.

Physical stability of the amorphous anticholesterol agent (ezetimibe): the role of molecular mobility.

The purpose of this paper is to examine the role of molecular mobility in the recrystallization process from the amorphous state of the anticholesterol drug ezetimibe. Both the molecular dynamics and crystallization kinetics have been studied using various experimental techniques, such as broadband dielectric spectroscopy (BDS), differential scanning calorimetry (DSC), and X-ray diffraction (XRD). Our investigations have shown that ezetimibe easily recrystallizes from the disordered state, both below and above its glass transition temperature (Tg = 336 K). Moreover, we found that an only slightly elevated pressure (5 MPa) significantly accelerates the recrystallization process at T > Tg. We predict that the structural relaxation time of amorphous ezetimibe at 293 K (storage temperature) and ambient pressure is only 22 days. This result corresponds to the characteristic time, determined from XRD measurements, for amorphous ezetimibe to recrystallize during storage at Troom = 298 K. It leads to the conclusion that the molecular mobility reflected in structural relaxation of ezetimibe is mainly responsible for devitrification of this drug. Finally, we determined a relatively easy way to improve the physical stability of the drug by preparing a binary amorphous ezetimibe-Soluplus mixture. Ezetimibe in an amorphous mixture with 20 wt % Soluplus has a much better (over six times) solubility than the pure crystalline material.

New insight into relaxation dynamics of an epoxy/hydroxy functionalized polybutadiene from dielectric and mechanical spectroscopy studies.

Dielectric and mechanical spectroscopy methods have been employed to describe the temperature dependencies of the segmental and macromolecular relaxation rates in epoxy/hydroxy functionalized polybutadiene. Dielectric studies on the dynamics of segments of the polymer as well as the mobility of small ions trapped in the system have been carried out both as a function of temperature and pressure under isobaric and isothermal conditions, respectively.

Stress fracture risk factors in basic combat training.

This study examined demographic and physical risk factors for stress fractures in a large cohort of basic trainees. New recruits participating in US Army BCT from 1997 through 2007 were identified, and birth year, race/ethnicity, physical characteristics, body mass index, and injuries were obtained from electronic databases. Injury cases were recruits medically diagnosed with inpatient or outpatient stress fractures. There were 475 745 men and 107 906 women. Stress fractures incidences were 19.3 and 79.9 cases/1 000 recruits for men and women, respectively. Factors that increased stress fracture risk for both men and women included older age, lower body weight, lower BMI, and race/ethnicity other than black. Compared to Asians, those of white race/ethnicity were at higher stress fractures risk. In addition, men, but not women, who were taller or heavier were at increased stress fracture risk. Stress fracture risk generally increased with age (17-35 year range) at a rate of 2.2 and 3.9 cases/1 000 recruits per year for men and women, respectively. This was the largest sample of military recruits ever examined for stress fractures and found that stress fracture risk was elevated among recruits who were female, older, had lower body weight, had lower BMI, and/or were not of black race/ethnicity.

Injuries before and after deployments to Afghanistan and Iraq.

OBJECTIVE: To examine outpatient injuries before and after deployments of elements of the 10th Mountain Division to Afghanistan (n = 505 men) and the 1st Cavalry Division to Iraq (n = 3242 men). STUDY DESIGN: Observational. METHODS: The military units provided a list of deployed soldiers, and soldiers' outpatient medical encounters were obtained from the Defense Medical Surveillance System. Cumulative injury incidence was examined for two consecutive 90-day periods before the deployments (Periods 1-2) and two consecutive 90-day periods after the deployments (Periods 3-4). RESULTS: Both groups showed post-deployment increases in the overall incidence of injury (Afghanistan group = 14.1%, 14.1%, 16.4, 23.4%; Iraq Group = 15.1%, 12.4%, 35.4%, 43.4%; Periods 1-4, respectively). Soldiers with pre-deployment injuries were 1.4-3.0 times more likely to experience post-deployment injuries. CONCLUSIONS: This study found a post-deployment increase in the incidence of outpatient injury. Also, soldiers with pre-deployment injuries were more likely to experience post-deployment injuries.

Risk factors associated with self-reported training-related injury before arrival at the US army ordnance school.

OBJECTIVE: This study examined risk factors for self-reported injury incurred before arrival at Ordnance School for advanced individual training (AIT). STUDY DESIGN: During AIT in-processing, soldiers (n=27,289 men and 3856 women) completed a questionnaire that collected demographic and lifestyle information, and asked if the soldier currently had an injury that would affect their AIT performance. METHODS: Potential risk factors for self-reported injury were explored using logistic regression. RESULTS: For men, self-reported injury was associated with older age [odds ratio (OR) >or=30 years/17-19 years=1.9], race (OR Black/Caucasian=1.2), basic combat training (BCT) site (OR Fort Benning/Fort Jackson=1.7; OR Fort Leonard Wood/Fort Jackson=1.6, OR Fort Knox/Fort Jackson=1.3), smoking on 20 or more days in the 30 days prior to BCT (OR smoker/non-smoker=1.2) and current illness (OR ill/not ill=6.2). For women, increased self-reported injury was associated with older age (OR>or=30 years/17-19 years=2.0), BCT site (OR Fort Leonard Wood/Fort Jackson=1.5) and current illness (OR ill/not ill=5.8). CONCLUSIONS: Certain demographic characteristics and lifestyle behaviours may be identified as injury risk factors on arrival at Ordnance AIT.

Ambulatory physical activity during United States Army basic combat training.

Electronic pedometers were used to quantify locomotor physical activity during an entire 9-week United States Army Basic Combat Training (BCT) cycle. Pedometers were worn on the hips of 4 trainees in each of 10 BCT companies during all BCT activities. Investigators obtained pedometer readings (steps) on a daily basis, and estimated travel distances were obtained by multiplying steps by the average individual step length. A short questionnaire was administered daily to assure trainees wore the pedometers and trained with their companies all day. Trainees performed an average +/- SD of 16 311 +/- 5826 steps/day and traveled an estimated 11.7 +/- 4.4 kilometers/day. The highest daily locomotor activity was during the field training exercise in which trainees took an average +/- SD of 22 372 +/- 12 517 steps/day traveling an estimated 16.2 +/- 9.7 kilometers/day. Differences among the 10 companies ranged from 14 720 +/- 6649 steps/day to 18 729 +/- 6328 steps/day. This survey provided the first examination of locomotor physical activity during an entire BCT cycle.

Influence of an injury reduction program on injury and fitness outcomes among soldiers.

OBJECTIVE: This study evaluated the influence of a multiple injury control intervention on injury and physical fitness outcomes among soldiers attending United States Army Ordnance School Advanced Individual Training. METHODS: The study design was quasiexperimental involving a historical control group (n = 2559) that was compared to a multiple intervention group (n = 1283). Interventions in the multiple intervention group included modified physical training, injury education, and a unit based injury surveillance system (UBISS). The management responsible for training independently formed an Injury Control Advisory Committee that examined surveillance reports from the UBISS and recommended changes to training. On arrival at school, individual soldiers completed a demographics and lifestyle questionnaire and took an army physical fitness test (APFT: push-ups, sit-ups, and two mile run). Injuries among soldiers were tracked by a clinic based injury surveillance system that was separate from the UBISS. Soldiers completed a final APFT eight weeks after arrival at school. RESULTS: Cox regression (survival analysis) was used to examine differences in time to the first injury while controlling for group differences in demographics, lifestyle characteristics, and physical fitness. The adjusted relative risk of a time loss injury was 1.5 (95% confidence interval 1.2 to 1.8) times higher in the historical control men and 1.8 (95% confidence interval 1.1 to 2.8) times higher in the historical control women compared with the multiple intervention men and women, respectively. After correcting for the lower initial fitness of the multiple intervention group, there were no significant differences between the multiple intervention and historical control groups in terms of improvements in push-ups, sit-ups, or two mile run performance. CONCLUSIONS: This multiple intervention program contributed to a reduction in injuries while improvements in physical fitness were similar to a traditional physical training program previously used at the school.

Injury and fitness outcomes during implementation of physical readiness training.

This study examined injury and physical fitness outcomes in Basic Combat Training (BCT) during implementation of Physical Readiness Training (PRT). PRT is the U.S. Army's emerging physical fitness training program. An experimental group (EG, n = 1284), which implemented the PRT program, was compared to a control group (CG, n = 1296), which used a traditional BCT physical training program during the 9-week BCT cycle. Injury cases were obtained from recruit medical records and physical fitness was measured using the U.S. Army Physical Fitness Test (APFT, consisting of push-ups, sit-ups and a two-mile run). Injury rates were examined using Cox regression after controlled for initial group differences in demographics, fitness and other variables. Compared to the EG, the adjusted relative risk of a time-loss overuse injury in the CG was 1.5 (95 % confidence interval [CI] = 1.0 - 2.1, p < 0.01) for men and 1.4 (95 %CI = 1.1 - 1.8, p < 0.01) for women. There were no differences between groups for traumatic injuries. On the first administration of the final APFT, the EG had a greater proportion of recruits passing the test than the CG (men: 85 % vs. 81 %, p = 0.04; women: 80 % vs. 70 %, p < 0.01). After all APFT retakes, the EG had significantly fewer APFT failures than the CG among the women (1.6 % vs. 4.6 %, p < 0.01) but not the men (1.6 % vs. 2.8 %, p = 0.18); the gender-combined EG had a higher pass rate (1.6 % vs. 3.7 %, p < 0.01). Overall, the PRT program reduced overuse injuries and allowed a higher success rate on the APFT.

The physical training and rehabilitation program: duration of rehabilitation and final outcome of injuries in basic combat training.

During calendar year 1998, 6% (N = 2,010: men [m] = 670, 3%, women [w] = 1,340, 12%) of soldiers in basic combat training at Fort Jackson, South Carolina (N = 32,251), were unable to continue training as a result of a training-related injury. These soldiers were recommended for the Physical Training and Rehabilitation Program (PTRP) for recovery and rehabilitation. Forty-two percent of recommended soldiers were discharged from the Army rather than assigned to PTRP. The 1,164 (m = 356, w = 808) soldiers assigned to PTRP sustained 1,673 injuries (m = 444, w = 1229). Eighty-three percent of the injuries in PTRP were in the overuse (44%) and stress fracture (39%) categories. Of the 1,164 soldiers assigned to PTRP, 52% (m = 214, w = 386) returned to training. The average (+/- SD) length of stay in PTRP for soldiers returning to duty was 62 +/- 42 days (m = 57 +/- 39, w = 65 +/- 43). Rehabilitation challenges and significant motivational issues presumably contributed to the 52% return to duty incidence for PTRP soldiers.

Angiotensin-converting enzyme genotype and physical performance during US Army basic training.

Prior studies have suggested that angiotensin I-converting enzyme (ACE) genotype correlates with superior physical performance in highly selected populations. This study assessed whether such an association exists in a heterogeneous population. Using polymerase chain reaction techniques, we determined the ACE genotypes (insertion/insertion, deletion/insertion, or deletion/deletion) of 62 male and 85 female US Army recruits. Before and after 8 wk of basic training, we determined peak oxygen uptake and performance on the Army Physical Fitness Test (APFT), which includes standardized measures of muscular endurance (sit-ups, push-ups) and a 2-mile run. Subjects of different ACE genotypes had similar peak oxygen uptakes and APFT scores, both before and after training. Subjects with genotype II had higher APFT scores than others, but the differences were not statistically significant. Furthermore, no ACE genotype group had a performance advantage in analyses that adjusted for baseline fitness. We conclude that ACE genotype does not have a strong effect on aerobic power or muscular endurance in healthy, young American adults drawn from an ethnically and geographically diverse population.

Aggressive uterine sarcoma with rhabdoid features: diagnosis by peritoneal fluid cytology and absence of INI1 gene mutation.

We report a primary uterine sarcoma with classic histologic, immunohistochemical, and ultrastructural features of a malignant extrarenal rhabdoid tumor (MERT). It arose in a 71-year-old woman who presented with postmenopausal bleeding, ascites, and a right pelvic mass. Malignant cells with rhabdoid morphology were identified by cytologic examination of the peritoneal fluid. Exploratory laparotomy revealed a 10-cm right adnexal mass and disseminated peritoneal tumor. Pathologic study showed diffuse expansion of the endometrial stroma by rhabdoid-like cells with transmural infiltration of the myometrium and extensive involvement of uterine serosa and right ovary by tumor. Neoplastic cells were immunoreactive for vimentin, cytokeratin, and epithelial membrane antigen, and cytoplasmic whorls of intermediate filaments were observed by electron microscopy. Fluorescence in situ hybridization (FISH) studies with chromosome 22-specific probes showed no loss of the INI1 gene, and no coding sequence mutation was identified.