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.

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.

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.

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.

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.

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.

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.

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 physical stability of neat amorphous RTV and RTV in hydroxypropylmethylcellulose acetate succinate solid dispersions was found to be mainly governed by the nucleation kinetic process. The impact of polymers and moisture on the crystallization process can be quantitatively described by Ea and b in this Arrhenius-type model. The good agreement between the measured values under some less stressful test conditions and those predicted, reflected by the slope and R(2) of the correlation plot of these 2 sets of data on a natural logarithm scale, indicates its predictability of long-term physical stability of amorphous RTV in solid dispersions. To further improve the model, more understanding of the impact of temperature and moisture on the amorphous physical stability and fundamentals regarding nucleation and crystallization is needed.

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). Because of these persistent issues and recent biophysical studies that have refined the debate ascribing meaning to the molecular dynamical transition temperature and Tg of protein molecules, we provide an updated discussion on the impact of assessing and managing localized, individual protein molecule nondiffusive motions in the context of proteins being prepared into bulk amorphous mixtures. Our aim is to bridge the pharmaceutical studies addressing bulk amorphous preparations and their glassy behavior, with the biophysical studies historically focused on the nondiffusive internal protein dynamics and a protein's activity, along with their combined efforts in assessing the impact of solvent hydrogen-bonding networks on local stability. We also provide recommendations for future research efforts in solid-state formulation approaches.

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. The in vitro factors compared primarily centered on dissolution testing and equipment, content and amount of dissolution media, sink or nonsink conditions, agitation rates, media pH, dissolution characteristics of the polymer, and dispersion particle size. The in vivo factors included reference materials used for bioavailability comparisons, animal species utilized, fasting versus fed conditions, and regional differences in gastrointestinal (GI) content and volume. On the basis of these considerations, a number of recommendations were made on issues ranging from the assessment of physical stability of API-polymer dispersions to in vivo GI physiological factors that require consideration in the performance evaluation of these systems.

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. The success of accelerated approaches to POC depends on a full understanding of the SSC of drugs in relation to solubility and stability. Dissolution-limited absorption due to poor solubility of drug substances is particularly important because it can lead to low exposure in animals and undesired bioavailability in humans. Choosing a desirable solid form with sufficient solubility and acceptable stability is essential in developing formulations for POC with superior quality. In this perspective we present an approach that utilizes SSC as part of a novel 2-year development strategy for reaching the pivotal clinical trial stage of development.

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. While the headgroup has a noticeable influence on the T(g), changing the chain length, on the other hand, has less of an impact. The values of the calorimteric T(g) were compared with other measures of molecular mobility in the PC species at comparable water contents reported in the literature. Observation of a T(g) in different phosphatidylethanolamines (PE), as previously reported, and PC species in this study suggests that a glass transition can be expected to be a common feature of biological membranes and phospholipid bilayer preparations, such as liposomes.

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 0.2 nm/s while samples similar to melt-cooled glasses were produced at 315 K and 5 nm/s. Samples deposited at 315 K absorb approximately the same amount of water as glasses prepared by supercooling the melt while stable glasses absorb a factor of 5 less water. Unexpectedly, the diffusion of water in the stable glass samples is 5-10 times faster than in the glass prepared by cooling the liquid.

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. Bioanal. Chem. 2003, 376, 182-188), of equilibrated KL 4, DPPC/KL 4, POPG/KL 4, and DPPC/POPG/KL 4 monolayers at the air-water interface was used to examine the in situ two-dimensional conformation of KL 4. Gravimetric vapor sorption by solid KL 4 was used to analyze the effects of water molecules on the conformation of KL 4 when confined as a monolayer at the surface of water. Solid-state KL 4 conformation was determined by X-ray powder diffraction (XRPD). The equilibrium interfacial and spreading properties were measured at 25 degrees C, 37 degrees C, and 45 degrees C using the Wilhelmy plate method and Langmuir film balance. Equilibrium phase transition temperatures were measured using differential scanning calorimetry (DSC). It was found that solid-state KL 4, which takes up very little water, exhibits beta-sheet and alpha-helix secondary structures, whereas KL 4 in solution appears to exist only as an alpha-helix. KL 4 forms a stable, insoluble monolayer, exhibiting beta-sheet and aperiodic structures. These structures provide KL 4, when confined in two-dimensions, the structural flexibility to maximize favorable cationic lysine-water interactions and favorable leucine-leucine hydrophobic and van der Waals interactions; while effectively "shielding" the leucine residues away from water. In DPPC/KL 4 monolayers, KL 4 retains its native beta-sheet and aperiodic structures, consistent with phase separation of DPPC and KL 4 in bilayers and monolayers. In POPG/KL 4 monolayers, KL 4 exhibits an increase in aperiodic secondary structures (loss of beta-sheet) to maximize favorable electrostatic interactions, consistent with the observed negative deviations from ideal monolayer mixing.

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. A lack of agreement of the PDF profiles indicates that the mixture with a unique PDF is miscible. In agreement with DSC measurements that detected two independent T(g) values for the dextran-PVP mixture, the PDF profiles of the mixture matched very well indicating a phase separated system. From the PDF analysis, indomethacin-PVP was shown to be completely miscible in agreement with the single T(g) value measured for the mixture. In the case of the trehalose-dextran mixture, where only one T(g) value was detected, however, PDF analysis clearly revealed phase separation. Since DSC can not detect two T(g) values when phase separation produces amorphous domains with sizes less than approximately 30 nm, it is concluded that the trehalose-dextran system is a phase separated mixture with a structure equivalent to a solid nanosuspension having nanosize domains. Such systems would be expected to have properties intermediate to those observed for miscible and macroscopically phase separated amorphous dispersions. However, since phase separation has occurred, the solid nanosuspensions would be expected to exhibit a greater tendency for physical instability under a given stress, that is, crystallization, than would a miscible system.