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, T). 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.

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.

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.

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) . 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 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.

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.

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 (T) 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 T values, conventional and modulated differential scanning calorimetry (DSC).

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.

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.

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, T, 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 T 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," T, (1.2-1.

Modeling Physical Stability of Amorphous Solids Based on Temperature and Moisture Stresses.

Isothermal microcalorimetry was utilized to monitor the crystallization process of amorphous ritonavir (RTV) and its hydroxypropylmethylcellulose acetate succinate-based amorphous solid dispersion under various stressed conditions. An empirical model was developed: ln(τ)=ln(A)+EaRT-b⋅wc, where τ is the crystallization induction period, A is a pre-exponential factor, Ea is the apparent activation energy, b is the moisture sensitivity parameter, and wc is water content. To minimize the propagation of errors associated with the estimates, a nonlinear approach was used to calculate mean estimates and confidence intervals.

The importance of individual protein molecule dynamics in developing and assessing solid state protein preparations.

Processing protein solutions into the solid state is a common approach for generating stable amorphous protein mixtures that are suitable for long-term storage. Great care is typically given to protecting the protein native structure during the various drying steps that render it into the amorphous solid state. However, many studies illustrate that chemical and physical degradations still occur in spite of this amorphous material having good glassy properties and it being stored at temperatures below its glass transition temperature (Tg).

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.

Assessing the performance of amorphous solid dispersions.

The characterization and performance of stable amorphous solid dispersion systems were evaluated in 40 research papers reporting active pharmaceutical ingredient (API) dissolution and bioavailability from various systems containing polymers. The results from these studies were broadly placed into three categories: amorphous dispersions that improved bioavailability (∼82% of the cases), amorphous dispersions possessing lower bioavailability than the reference material (∼8% of the cases), and amorphous dispersions demonstrating similar bioavailabilities as the reference material (∼10% of the cases). A comparative analysis of these studies revealed several in vitro and in vivo variables that could have influenced the results.

Accelerating proof of concept for small molecule drugs using solid-state chemistry.

In this perspective we have shown that the process of "proof of concept" (POC) in the early part of drug development can be greatly accelerated by close attention to the underlying solid-state chemistry (SSC) of a new chemical entity. POC seeks data that provide confidence in the therapeutic activity and safety of a new chemical entity, which can rapidly lead to a key "GO/NO-GO" decision point for further development. Due to the high cost of the development of new chemical entities and the current low overall productivity of obtaining successful candidates, the pharmaceutical industry is being required to develop accelerated POC strategies.

Occurrence of glass transitions in long-chain phosphatidylcholine mesophases.

Several phosphatidylcholine (PC) species were studied by differential scanning calorimetry at different levels of hydration. A glass transition was observed in both lamellar gel and nonlamellar phases, with the glass transition temperature, T(g), decreasing as water content was increased. The structure of the lipid mesophase has a major impact on T(g), with the lamellar gel phase having a higher T(g) than that of nonlamellar phases of the same lipid.

Highly stable indomethacin glasses resist uptake of water vapor.

Mass uptake of water vapor was measured as a function of relative humidity for indomethacin glasses prepared using physical vapor deposition at different substrate temperatures. Highly stable glasses were produced on substrates at 265 K (0.84Tg) by depositing at 0.

Characterization of the in situ structural and interfacial properties of the cationic hydrophobic heteropolypeptide, KL4, in lung surfactant bilayer and monolayer models at the air-water interface: implications for pulmonary surfactant delivery.

This study examines the various equilibrium in situ secondary structures of the pharmaceutical heteropolypeptide, KL 4, in the solid state, in solution, and in the monolayer state alone and mixed with dipalmitoylphosphatidylcholine (DPPC) and palmitoyloleoylphosphatidylglycerol (POPG). In situ surface circular dichroism spectroscopy, using a method first reported by Damodaran (Damodaran, S. Anal.

Characterization of amorphous API:Polymer mixtures using X-ray powder diffraction.

Recognizing limitations with the standard method of determining whether an amorphous API-polymer mixture is miscible based on the number of glass transition temperatures (T(g)) using differential scanning calorimetry (DSC) measurements, we have developed an X-ray powder diffraction (XRPD) method coupled with computation of pair distribution functions (PDF), to more fully assess miscibility in such systems. The mixtures chosen were: dextran-poly(vinylpyrrolidone) (PVP) and trehalose-dextran, both prepared by lyophilization; and indomethacin-PVP, prepared by evaporation from organic solvent. Immiscibility is detected when the PDF profiles of each individual component taken in proportion to their compositions in the mixture agree with the PDF of the mixture, indicating phase separation into independent amorphous phases.

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.

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.

Relationships between equilibrium spreading pressure and phase equilibria of phospholipid bilayers and monolayers at the air-water interface.

The intricate interplay between the bilayer and monolayer properties of phosphatidylcholine (PC), phosphatidylglycerol (PG), and phosphatidylethanolamine (PE) phospholipids, in relation to their polar headgroup properties, and the effects of chain permutations on those polar headgroup properties have been demonstrated for the first time with a set of time-independent bilayer-monolayer equilibria studies. Bilayer and monolayer phase behavior for PE is quite different than that observed for PC and PG. This difference is attributed to the characteristic biophysical PE polar headgroup property of favorable intermolecular hydrogen-bonding and electrostatic interactions in both the bilayer and monolayer states.

The relationship between water vapor absorption and desorption by phospholipids and bilayer phase transitions.

Water vapor absorption and desorption at 25 degrees C and phase transition temperatures of phospholipid bilayers were measured as a function of relative humidity (RH) to better understand how the patterns of water vapor absorption and desorption are linked to corresponding phase changes induced by the level of hydration. Comparisons were made of the dipalmitoyl and palmitoyloleyol esters of glycerol derivatized with phosphatidyl-choline, -glycerol, -ethanolamine and with phosphatidic acid. The results suggest that the extent of water vapor absorption and desorption at a given RH reflects the combined effects of water-polar group interaction and access of water to the polar region as controlled by intra- and interbilayer molecular packing and intermolecular attractive and repulsive interactions.

Analysis of amorphous and nanocrystalline solids from their X-ray diffraction patterns.

Purpose: The purpose of this paper is to provide a physical description of the amorphous state for pharmaceutical materials and to investigate the pharmaceutical implications. Techniques to elucidate structural differences in pharmaceutical solids exhibiting characteristic X-ray amorphous powder patterns are also presented.

Materials And Methods: The X-ray amorphous powder diffraction patterns of microcrystalline cellulose, indomethacin, and piroxicam were measured with laboratory XRPD instrumentation.