Perspectives on the Wetting of Solids in Pharmaceutical Systems.

PURPOSE: The ability of water and aqueous solutions to wet relatively nonpolar pharmaceutical solids during the processing and administration of solid dosage forms is an important part of development. RESULTS: Various factors, both fundamental and technological, which are important to wettability are reviewed and analyzed. Initially, the ideal thermodynamic importance of liquid surface tension and solid surface energetics, determined by the contact angle and the polarity of the solid surface, are established. Then, emphasis is placed on various factors that change the surface energetics due to crystal defects, polymorphism, varying Miller Indices, crystal habit, amorphous structure, variable surface concentration of components in a formulation mixture, surface roughness, and complex pore structure. Case studies cover single component systems (APIs and excipients), binary mixtures (amorphous solid dispersions and physical mixtures), multicomponent systems (granules and tablets), as well as disintegration and dissolution of solid oral dosage forms. CONCLUSIONS: This perspective and analysis indicates the primary importance of understanding and modifying solid surface energetics, surface chemical and physical heterogeneities, and pore structure to promote wettability in pharmaceutical systems.

What Are the Important Factors That Influence API Crystallization in Miscible Amorphous API-Excipient Mixtures during Long-Term Storage in the Glassy State?

In this Perspective, the authors examine the various factors that should be considered when attempting to use miscible amorphous API-excipient mixtures (amorphous solid dispersions and coamorphous systems) to prevent the solid-state crystallization of API molecules when isothermally stored for long periods of time (a year or more) in the glassy state. After presenting an overview of a variety of studies designed to obtain a better understanding of possible mechanisms by which amorphous API undergo physical instability and by which excipients generally appear to inhibit API crystallization from the amorphous state, we examined 78 studies that reported acceptable physical stability of such systems, stored below Tg under "dry" conditions for one year or more. These results were examined more closely in terms of two major contributing factors: the degree to which a reduction in diffusional molecular mobility and API-excipient molecular interactions operates to inhibit crystallization. These two parameters were chosen because the data are readily available in early development to help compare amorphous systems. Since Tg - T = 50 K is often used as a rule of thumb for the establishing the minimum value below Tg required to reduce diffusional mobility to a period of years, it was interesting to observe that 30 of the 78 studies still produced significant physical stability at values of Tg - T < 50 K (3-47 °C), suggesting that factors besides diffusive molecular mobility likely contribute. A closer look at the Tg - T < 50 systems shows that hydrogen bonding, proton transfer, disruption of API-API self-associations (such as dimers), and possible π-π stacking were reported for most of the systems. In contrast, five crystallized systems that were monitored for a year or more were also examined. These systems exhibited Tg - T values of 9-79, with three of them exhibiting Tg - T < 50. For these three samples, none displayed molecular interactions by infrared spectroscopy. A discussion on the impact of relative humidity on long-term crystallization in the glass was included, with attention paid to the relative water vapor sorption by various excipients and effects on diffusive mobility and molecular interactions between API and excipient.

What We Need to Know about Solid-State Isothermal Crystallization of Organic Molecules from the Amorphous State below the Glass Transition Temperature.

In this Perspective, the authors have examined various principles associated with the isothermal crystallization of organic molecules from the amorphous state. The major objective was to better understand the underlying principles influencing long-term crystallization from the glassy state at temperatures sufficiently low enough to prevent crystallization over a period of about 2-3 years; this time frame was chosen based on the requirements for ensuring the physical stability of solid drug products. As such, after considering the general thermodynamic, dynamic (molecular mobility), and structural properties of both supercooled liquids and glasses, current understanding from the literature of overall crystallization, nucleation and growth from glasses, was reviewed. Typically, in attempting to establish the appropriate storage temperature, T, in the glassy state, relative to the glass transition temperature, Tg, i.e., Tg - T, most studies have tended to emphasize the rates of bulk diffusional molecular mobility of molecules at such temperatures and classical crystal nucleation and growth theory. However, a closer analysis of factors affecting crystallization from the glassy state revealed that greater consideration should be given to other contributing factors, including methods of producing the glass, heterogeneous nucleation due to processing conditions, secondary Johari-Goldstein relaxations, nondiffusional crystal growth in the glass (GC-growth), and surface crystallization.

Commentary: Considerations in the Measurement of Glass Transition Temperatures of Pharmaceutical Amorphous Solids.

An increased interest in using amorphous solid forms in pharmaceutical applications to increase solubility, dissolution, and bioavailability has generated a need for better characterization of key properties, such as the glass transition (Tg) temperature. Although many laboratories measure and report this value, the details around these measurements are often vague or misunderstood. In this article, we attempt to highlight and compare various aspects of the two most common methods used to measure pharmaceutical Tg values, conventional and modulated differential scanning calorimetry (DSC). Issues that directly impact the Tg, such as instrumental parameters, sample preparation methods, data analysis, and "wet" vs. "dry" measurements, are discussed.

Structural Features of the Glassy State and Their Impact on the Solid-State Properties of Organic Molecules in Pharmaceutical Systems.

This paper reviews the structure and properties of amorphous active pharmaceutical ingredients (APIs), including small molecules and proteins, in the glassy state (below the glass transition temperature, Tg). Amorphous materials in the neat state and formulated with excipients as miscible amorphous mixtures are included, and the role of absorbed water in affecting glass structure and stability has also been considered. We defined the term "structure" to indicate the way the various molecules in a glass interact with each other and form distinctive molecular arrangements as regions or domains of varying number of molecules, molecular packing, and density. Evidence is presented to suggest that such systems generally exist as heterogeneous structures made up of high-density domains surrounded by a lower density arrangement of molecules, termed the microstructure. It has been shown that the method of preparation and the time frame for handling and storage can give rise to variable glass structures and varying physical properties. Throughout this paper, examples are given of theoretical, computer simulation, and experimental studies which focus on the nature of intermolecular interactions, the size of heterogeneous higher density domains, and the impact of such systems on the relative physical and chemical stability of pharmaceutical systems.

Considerations in the Development of Physically Stable High Drug Load API- Polymer Amorphous Solid Dispersions in the Glassy State.

In this Commentary, the authors expand on their earlier studies of the solid-state long-term isothermal crystallization of amorphous API from the glassy state in amorphous solid dispersions, and focus on the effects of polymer concentration, and its implications for producing high load API doses with minimum polymer concentration. After presenting an overview of the various mechanistic factors which influence the ability of polymers to inhibit API crystallization, including the chemical structure of the polymer relative to the API, the nature and strength of API-polymer noncovalent interactions, polymer molecular weight, impact on primary diffusive molecular mobility, as well as on secondary motions in the bulk and surface phases of the glass, we consider in more detail, the effects of polymer concentration. Here, we examine the factors that appear to allow relatively low polymer concentrations, i.e., less than 10%w/w polymer, to greatly reduce crystallization, including a focus on the heterogeneous structure of the glassy state, and the possible spatial distribution and concentration of polymer in certain key regions of the glass. This is followed by a review and analysis of examples in the recent literature focused on determining the minimum polymer concentration in an amorphous solid dispersion, capable of producing optimally stable high drug load amorphous dispersions.

An Examination of Water Vapor Sorption by Multicomponent Crystalline and Amorphous Solids and Its Effects on Their Solid-State Properties.

This commentary critically evaluated the unique effects of water vapor sorption by multicomponent solid forms of active pharmaceutical ingredients (APIs), and its effects on their physical and chemical properties. Such multicomponent forms include the following: (1) crystalline salts and cocrystals, and (2) amorphous salts, coamorphous mixtures, and amorphous solid dispersions (ASDs). These solid forms are commonly used to increase the solubility, dissolution, and bioavailability of poorly soluble APIs. To achieve this increase, selected counterions or coformers exhibit much greater polarity, and have a tendency to enhance water vapor sorption, leading to possible instabilities. Such instabilities include salt disproportionation, cocrystal dissociation, and phase separation and crystallization from amorphous forms. Regarding crystalline multicomponent systems, significant instabilities arise on account of deliquescence or crystal hydrate formation. Such behavior often follows water-induced salt disproportionation or cocrystal dissociation. Regarding amorphous salts, coamorphous mixtures, and ASDs, we see the importance of absorbed water as a disrupter of API-coformer interactions and as a plasticizer in bringing about subsequent phase separation and crystallization. In preparing multicomponent solid forms, it is important to measure the water vapor sorption isotherm of the counterion or coformer to better understand the mode by which water is sorbed, and to anticipate and correct possible instabilities.

Dietary protein intake is not associated with 5-y change in mid-thigh muscle cross-sectional area by computed tomography in older adults: the Health, Aging, and Body Composition (Health ABC) Study.

BACKGROUND: A higher protein intake is suggested to preserve muscle mass during aging and may therefore reduce the risk of sarcopenia. OBJECTIVES: We explored whether the amount and type (animal or vegetable) of protein intake were associated with 5-y change in mid-thigh muscle cross-sectional area (CSA) in older adults (n = 1561). METHODS: Protein intake was assessed at year 2 by a Block food-frequency questionnaire in participants (aged 70-79 y) of the Health, Aging, and Body Composition (Health ABC) Study, a prospective cohort study. At year 1 and year 6 mid-thigh muscle CSA in square centimeters was measured by computed tomography. Multiple linear regression analysis was used to examine the association between energy-adjusted protein residuals in grams per day (total, animal, and vegetable protein) and muscle CSA at year 6, adjusted for muscle CSA at year 1 and potential confounders including prevalent health conditions, physical activity, and 5-y change in fat mass. RESULTS: Mean (95% CI) protein intake was 0.90 (0.88, 0.92) g · kg-1 · d-1 and mean (95% CI) 5-y change in muscle CSA was -9.8 (-10.6, -8.9) cm2. No association was observed between energy-adjusted total (ß = -0.00; 95% CI: -0.06, 0.06 cm2; P = 0.982), animal (ß = -0.00; 95% CI: -0.06, 0.05 cm2; P = 0.923), or plant (ß = +0.07; 95% CI: -0.06, 0.21 cm2; P = 0.276) protein intake and muscle CSA at year 6, adjusted for baseline mid-thigh muscle CSA and potential confounders. CONCLUSIONS: This study suggests that a higher total, animal, or vegetable protein intake is not associated with 5-y change in mid-thigh muscle CSA in older adults. This conclusion contradicts some, but not all, previous research. This trial was registered at www.trialregister.nl as NTR6930.

Characterization of the "hygroscopic" properties of active pharmaceutical ingredients.

The amount of water vapor taken up by an active pharmaceutical ingredient (API) as a function of relative humidity is routinely evaluated to characterize and monitor its "hygroscopicity" throughout the drug development process. In this minireview we address the necessity of going beyond the measurement of water vapor sorption isotherms to establish the various mechanisms by which solids interact with water and the important role played by the crystalline or amorphous form of the solid. Practical approaches for choosing experimental conditions under which water vapor sorption should be measured, including the pre-treatment of samples and the time allowed to reach an equilibrium state are presented. With the assistance of a flowchart, we provide a basis for the systematic examination of samples to establish the likely mechanisms of sorption and the indicators pointing toward future problems with physical and chemical instabilities. Finally, we present strategies for managing materials that might be susceptible to the detrimental effects of water vapor sorption.

Coamorphous Active Pharmaceutical Ingredient-Small Molecule Mixtures: Considerations in the Choice of Coformers for Enhancing Dissolution and Oral Bioavailability.

In the recent years, coamorphous systems, containing an active pharmaceutical ingredient (API) and a small molecule coformer have appeared as alternatives to the use of either amorphous solid dispersions containing polymer or cocrystals of API and small molecule coformers, to improve the dissolution and oral bioavailability of poorly soluble crystalline API. This Commentary article considers the relative properties of amorphous solid dispersions and coamorphous systems in terms of methods of preparation; miscibility; glass transition temperature; physical stability; hygroscopicity; and aqueous dissolution. It also considers important questions concerning the fundamental criteria to be used for the proper selection of a small molecule coformer regarding its ability to form either coamorphous or cocrystal systems. Finally, we consider various aspects of product development that are specifically associated with the formulation of commercial coamorphous systems as solid oral dosage forms. These include coformer selection; screening; methods of preparation; preformulation; physical stability; bioavailability; and final formulation. Through such an analysis of coamorphous API-small molecule coformer systems, against the more widely studied API-polymer dispersions and cocrystals, it is believed that the strengths and weaknesses of coamorphous systems can be better understood, leading to more efficient formulation and manufacture of such systems for enhancing oral bioavailability.

Assessment of defects and amorphous structure produced in raffinose pentahydrate upon dehydration.

The progressive conversion of crystalline raffinose pentahydrate to its amorphous form by dehydration at 60 degrees C, well below its melting temperature, was monitored by X-ray powder diffraction over a period of 72 h. The presence of defects within the crystal structure and any amorphous structure created was determined computationally by a total diffraction method where both coherent long-range crystalline order and incoherent short-range disorder components were modeled as a single system. The data were analyzed using Rietveld, pair distribution function (PDF), and Debye total diffraction methods. Throughout the dehydration process, when crystalline material was observed, the average long-range crystal structure remained isostructural with the original pentahydrate material. Although the space group symmetry remained unchanged by dehydration, the c-axis of the crystal unit cell exhibited an abrupt discontinuity after approximately 2 h of drying (loss of one to two water molecules). Analysis of diffuse X-ray scattering revealed an initial rapid build up of defects during the first 0.5 h with no evidence of any amorphous material. From 1-2 h of drying out to 8 h where the crystalline structure is last observed, the diffuse scattering has both amorphous and defect contributions. After 24 h of drying, there was no evidence of any crystalline material remaining. It is concluded that the removal of the first two waters from raffinose pentahydrate created defects, likely in the form of vacancies, that provided the thermodynamic driving force and disorder for subsequent conversion to the completely amorphous state.

Obesity in older adults: synthesis of findings and recommendations for clinical practice.

Obesity is a serious condition that often complicates chronic health conditions in older adults, making health promotion a challenge. Growing numbers of older adults means the number of older adults who are obese also will increase. Various authors have provided important information related to obesity and related complications in older adults; however, practical guidelines specific to nursing are lacking. This article summarizes and relates the findings on older adult obesity and provides suggestions for nursing interventions aimed at reducing obesity in older adults.

Arthritis and sexuality.

More than 120 kinds of arthritis exist. This article focuses on the more common types of musculoskeletal disorders, which are osteoarthritis, rheumatoid arthritis, and osteoporosis. Because of the pain, fatigue, and joint stiffness associated with arthritis, physical intimacy may be difficult. These symptoms can be ameliorated during sexual activity by good communication between the partners, timing medication, and experimenting with different positions. Clients may need to be taught to be creative and to be willing to experiment. Learning the relaxation response, in addition to fantasizing and guided imagery, can enhance the sexual experience for people who have arthritis.

Interrelationships Between Structure and the Properties of Amorphous Solids of Pharmaceutical Interest.

This commentary explores fundamental issues associated with the structure of amorphous solids of pharmaceutical interest in terms of the effects of such structure on: various thermodynamic properties; the glass transition temperature, Tg, physical aging of glasses, polyamorphism; molecular mobility by primary diffusive and secondary Johari-Goldstein relaxations; solid-state crystallization; water vapor absorption; and the formation of active pharmaceutical ingredients-polymer dispersions. Recognizing that small organic molecules, as well as polymers used pharmaceutically, tend to exhibit highly "fragile" behavior in the supercooled liquid state, that is, significant increases in relaxation time or viscosity with decreasing temperature as Tg is approached, particular emphasis has been placed on local and global structural factors, that appear to give rise to the nonexponential dependence of the structural relaxation time and viscosity associated with spatial and temporal heterogeneity, at temperatures below the "crossover temperature," Tx, (1.2-1.4 Tg), using theoretical random close packing and "jamming" models. Utilizing a "2-region" structural model of the glassy state, wherein glasses consist of clustered domains surrounded by a higher energy and less dense "microstructure," it has been possible to better understand the underlying structural factors that give rise to a number of important phenomena which occur in the glassy state.

Dynapenia and Metabolic Health in Obese and Nonobese Adults Aged 70 Years and Older: The LIFE Study.

OBJECTIVE: The purpose of this study was to examine the relationship between dynapenia and metabolic risk factors in obese and nonobese older adults. METHODS: A total of 1453 men and women (age ≥70 years) from the Lifestyle Interventions and Independence for Elders (LIFE) Study were categorized as (1) nondynapenic/nonobese (NDYN-NO), (2) dynapenic/nonobese (DYN-NO), (3) nondynapenic/obese (NDYN-O), or (4) dynapenic/obese (DYN-O), based on muscle strength (Foundation for the National Institute of Health criteria) and body mass index. Dependent variables were blood lipids, fasting glucose, blood pressure, presence of at least 3 metabolic syndrome (MetS) criteria, and other chronic conditions. RESULTS: A significantly higher likelihood of having abdominal obesity criteria in NDYN-NO compared with DYN-NO groups (55.6 vs 45.1%, P ≤ .01) was observed. Waist circumference also was significantly higher in obese groups (DYN-O = 114.0 ± 12.9 and NDYN-O = 111.2 ± 13.1) than in nonobese (NDYN-NO = 93.1 ± 10.7 and DYN-NO = 92.2 ± 11.2, P ≤ .01); and higher in NDYN-O compared with DYN-O (P = .008). Additionally, NDYN-O demonstrated higher diastolic blood pressure compared with DYN-O (70.9 ± 10.1 vs 67.7 ± 9.7, P ≤ .001). No significant differences were found across dynapenia and obesity status for all other metabolic components (P > .05). The odds of having MetS or its individual components were similar in obese and nonobese, combined or not with dynapenia (nonsignificant odds ratio [95% confidence interval]). CONCLUSION: Nonobese dynapenic older adults had fewer metabolic disease risk factors than nonobese and nondynapenic older adults. Moreover, among obese older adults, dynapenia was associated with lower risk of meeting MetS criteria for waist circumference and diastolic blood pressure. Additionally, the presence of dynapenia did not increase cardiometabolic disease risk in either obese or nonobese older adults.

Association of sleep time with diabetes mellitus and impaired glucose tolerance.

BACKGROUND: Experimental sleep restriction causes impaired glucose tolerance (IGT); however, little is known about the metabolic effects of habitual sleep restriction. We assessed the cross-sectional relation of usual sleep time to diabetes mellitus (DM) and IGT among participants in the Sleep Heart Health Study, a community-based prospective study of the cardiovascular consequences of sleep-disordered breathing. METHODS: Participants were 722 men and 764 women, aged 53 to 93 years. Usual sleep time was obtained by standardized questionnaire. Diabetes mellitus was defined as a serum glucose level of 126 mg/dL or more (> or =7.0 mmol/L) fasting or 200 mg/dL or more (> or =11.1 mmol/L) 2 hours following standard oral glucose challenge or medication use for DM. Impaired glucose tolerance was defined as a 2-hour postchallenge glucose level of 140 mg/dL or more (> or =7.8 mmol/L) and less than 200 mg/dL. The relation of sleep time to DM and IGT was examined using categorical logistic regression with adjustment for age, sex, race, body habitus, and apnea-hypopnea index. RESULTS: The median sleep time was 7 hours per night, with 27.1% of subjects sleeping 6 hours or less per night. Compared with those sleeping 7 to 8 hours per night, subjects sleeping 5 hours or less and 6 hours per night had adjusted odds ratios for DM of 2.51 (95% confidence interval, 1.57-4.02) and 1.66 (95% confidence interval, 1.15-2.39), respectively. Adjusted odds ratios for IGT were 1.33 (95% confidence interval, 0.83-2.15) and 1.58 (95% confidence interval, 1.15-2.18), respectively. Subjects sleeping 9 hours or more per night also had increased odds ratios for DM and IGT. These associations persisted when subjects with insomnia symptoms were excluded. CONCLUSIONS: A sleep duration of 6 hours or less or 9 hours or more is associated with increased prevalence of DM and IGT. Because this effect was present in subjects without insomnia, voluntary sleep restriction may contribute to the large public health burden of DM.

Amorphous solid dispersions: a robust platform to address bioavailability challenges.

Amorphous solid dispersions (ASDs) are being used with increasing frequency for poorly soluble pharmaceutical compounds in development. These systems consist of an amorphous active pharmaceutical ingredient stabilized by a polymer to produce a system with improved physical and solution stability. ASDs are commonly considered as a means of improving the apparent solubility of an active pharmaceutical ingredient. This review will discuss methods of preparation and characterization of ASDs with an emphasis on understanding and predicting stability. Theoretical understanding of supersaturation and predicting in vivo performance will be stressed. Additionally, a summary of preclinical and clinical development efforts will be presented to give the reader an understanding of risks and key pitfalls when developing an ASD.

Solid-state analysis of the active pharmaceutical ingredient in drug products.

The solid form of a drug substance is important when developing a new chemical entity. The crystalline form used in development is significant based on possible manufacturability, solubility, bioavailability and stability differences between the solid forms. Regulatory issues require that the form present in a solid dosage form or liquids containing undissolved drug substance be identified. Drug product samples can be analyzed by a variety of techniques to determine the crystal form present or changes that occur during the manufacture of a drug product. The form present will affect development, regulatory and intellectual property issues.

Critical considerations for the qualitative and quantitative determination of process-induced disorder in crystalline solids.

Solid-state instabilities in crystalline solids arise during processing primarily because a certain level of structural disorder has been introduced into the crystal. Many physical instabilities appear to be associated with the recrystallization of molecules from these disordered regions, while chemical instabilities arise from sufficient molecular mobility to allow solid-state chemical reactivity. In this Commentary we discuss the various forms of structural disorder, processing which can produce disorder, the quantitative analysis of process-induced order, and strategies to limit disorder and its effects.