Amorphous pharmaceutical solids: preparation, characterization and stabilization

The importance of amorphous pharmaceutical solids lies in their useful properties, common occurrence, and physicochemical instability relative to corresponding crystals. Some pharmaceuticals and excipients have a tendency to exist as amorphous solids, while others require deliberate prevention of crystallization to enter and remain in the amorphous state. Amorphous solids can be produced by common pharmaceutical processes, including melt quenching, freeze- and spray-drying, milling, wet granulation, and drying of solvated crystals. The characterization of amorphous solids reveals their structures, thermodynamic properties, and changes (crystallization and structural relaxation) in single- and multi-component systems. Current research in the stabilization of amorphous solids focuses on: (i) the stabilization of labile substances (e.g., proteins and peptides) during processing and storage using additives, (ii) the prevention of crystallization of the excipients that must remain amorphous for their intended functions, and (iii) the selection of appropriate storage conditions under which amorphous solids are stable.     

Raman spectroscopy for quantitative analysis of pharmaceutical solids

Raman spectroscopy is experiencing a surge in interest in solid-state pharmaceutical applications. It is rapid, non-destructive, no sample preparation is required and measurements can be made in aqueous environments. It can be used for not only qualitative, but also quantitative, analysis. In this paper, the use of Raman spectroscopy for quantitative analysis of pharmaceutical solids is reviewed. The technique has been used for chemical and physical form analysis. Physical form analysis has involved quantification of polymorphism, hydrates, the amorphous form and, recently, protein conformation. Initially, simple powder systems were quantified, although this has since extended to complex pharmaceutical formulations, including tablets, capsules, microspheres and suspensions. Formulations have also been analysed through packaging. The characteristics of the technique make it ideal for process monitoring and it has been used to quantify changes in-situ during processes such as wet granulation and batch crystallisation. The theoretical basis of quantitative Raman spectroscopy, common data analysis approaches, including multivariate analysis, and sources of error in quantitative analysis are also discussed.     

Community pharmacists' perspectives on pharmaceutical care implementation in New Zealand

Objective: There were three objectives to this study: to establish New Zealand community pharmacists' level of understanding of the pharmaceutical care process; to determine their attitudes to the concept of pharmaceutical care; and to determine the barriers to commencing pharmaceutical care practice. Comparisons were made between proprietors (pharmacy owners) and employees, males and females, and younger and older pharmacists. Method: The research tool was a questionnaire instrument, encompassing a total of 67 questions designed to determine community pharmacists' understanding, attitudes and appreciation of the opportunities and barriers inherent in the pharmaceutical care process. A total of 490 pharmacists representing 286 proprietors and 204 employees randomly selected from the Pharmaceutical Society register were sent a questionnaire. Results: The total responses numbered 377, which was a 76.9% overall response rate. Over 60% of the pharmacists surveyed had a correct understanding of pharmaceutical care. Approximately the same percentage felt the future of pharmacy would depend on the provision of services other than dispensing. Insufficient time, as a barrier to implementation, was identified by 87% of respondents, and an absence of a reimbursement system by a further 82%. Lack of: therapeutic knowledge; clinical problem solving skills; finance; appropriate space; patient demand; access to patient medical records; and data on the value of PC were identified as major barriers by over 50% of all respondents. There were significant differences in response to a number of issues recorded by males and females, proprietors and employees, and pharmacists above and below the mean sample age of 45 years.Conclusion: This study found that the community pharmacy environment in New Zealand had a high level of understanding of the pharmaceutical care process, but identified some significant barriers to implementation.     

Community pharmacists'' perspectives on pharmaceutical care implementation in New Zealand

Objective: There were three objectives to this study: to establish New Zealand community pharmacists' level of understanding of the pharmaceutical care process; to determine their attitudes to the concept of pharmaceutical care; and to determine the barriers to commencing pharmaceutical care practice. Comparisons were made between proprietors (pharmacy owners) and employees, males and females, and younger and older pharmacists. Method: The research tool was a questionnaire instrument, encompassing a total of 67 questions designed to determine community pharmacists' understanding, attitudes and appreciation of the opportunities and barriers inherent in the pharmaceutical care process. A total of 490 pharmacists representing 286 proprietors and 204 employees randomly selected from the Pharmaceutical Society register were sent a questionnaire. Results: The total responses numbered 377, which was a 76.9% overall response rate. Over 60% of the pharmacists surveyed had a correct understanding of pharmaceutical care. Approximately the same percentage felt the future of pharmacy would depend on the provision of services other than dispensing. Insufficient time, as a barrier to implementation, was identified by 87% of respondents, and an absence of a reimbursement system by a further 82%. Lack of: therapeutic knowledge; clinical problem solving skills; finance; appropriate space; patient demand; access to patient medical records; and data on the value of PC were identified as major barriers by over 50% of all respondents. There were significant differences in response to a number of issues recorded by males and females, proprietors and employees, and pharmacists above and below the mean sample age of 45 years.Conclusion: This study found that the community pharmacy environment in New Zealand had a high level of understanding of the pharmaceutical care process, but identified some significant barriers to implementation.     

A material science perspective of pharmaceutical solids

This review introduces the basic material science concepts and principles behind some common topics in the development of pharmaceutical solid formulations. The physiochemical properties of small organic pharmaceutical materials are summarized. Common phases, differences in phases, phase transitions, and their relation to pharmaceutical development are reviewed. The characteristics and physical nature of solid phases, including crystalline and amorphous solids, are presented in conjunction with some pharmaceutically relevant phenomena, such as polymorphism, phase transition kinetics, and relaxation. Mesophases, including liquid crystals and condis crystals, are introduced. The potential energy states of different phases are highlighted as the key connection between the physical nature of the materials and their pharmaceutical behavior, and energy landscape is employed to enhance the understanding of this relation.     

Critical surface tensions of pharmaceutical solids.

Advancing contact angles measured on compacts of several drugs by the sessile drop method and also by penetration through a column of drug granules were used to find the critical surface tension of the drugs. After liquid was delivered at a very slow rate, the contact angle of sessile drops decreased with time, but use of a consistent method of timing always led to the same value for critical surface tension. Results from penetration studies and work on compacts were in agreement, provided that the surfaces of the compacts were smooth and highly reflective. Critical surface tension of the six drugs, three analgesics and three sulfonamides, ranged from 31 to 33 dynes/cm. The critical surface tension of mixtures of phenacetin and microcrystalline cellulose was not a linear function of the relative surface fractions of the two materials. If the surface contained 25% or more of phenacetin, the critical surface tension barely differed from that of pure phenacetin.     

New perspectives for the on-line monitoring of pharmaceutical crystallization processes using in situ infrared spectroscopy

Chemists and engineers involved in the industrial production of solid drugs have to deal with difficult new challenges, including the on-line mastery of the crystal habits and size distribution, the control of polymorphic transitions or the improvement of the chemical purity. A major limitation to improving the control of industrial crystallizers lies in the lack of versatile, accurate and reliable on-line sensors. It is shown that supersaturation measurements can be performed using in situ ATR mid-infrared spectroscopy thus providing valuable real-time information about the crystallization process. Several case studies are presented to illustrate new potential applications of the technique. The reported experimental results outline recent advances in the acquisition of key data characterizing the solute/solvent system in question (i.e. solubility, metastability, phase transformations...), the design of on-line control strategies capable of improving both the crystal size distribution (CSD) and the reproducibility of the quality of the final product, the assessment of improved operating strategies (e.g. seeding batch crystallizers), and the monitoring of polymorphic transitions during cooling crystallization operations. The possibility of evaluating on-line the process impurities, which could allow the reduction of batch-to-batch variations of the quality of the solid product, is also briefly envisaged.     

A novel accelerated oxidative stability screening method for pharmaceutical solids

Despite the fact that oxidation is the second most frequent degradation pathway for pharmaceuticals, means of evaluating the oxidative stability of pharmaceutical solids, especially effective stress testing, are still lacking. This paper describes a novel experimental method for peroxide-mediated oxidative stress testing on pharmaceutical solids. The method utilizes urea-hydrogen peroxide, a molecular complex that undergoes solid-state decomposition and releases hydrogen peroxide vapor at elevated temperatures (e.g., 30°C), as a source of peroxide. The experimental setting for this method is simple, convenient, and can be operated routinely in most laboratories. The fundamental parameter of the system, that is, hydrogen peroxide vapor pressure, was determined using a modified spectrophotometric method. The feasibility and utility of the proposed method in solid form selection have been demonstrated using various solid forms of ephedrine. No degradation was detected for ephedrine hydrochloride after exposure to the hydrogen peroxide vapor for 2 weeks, whereas both anhydrate and hemihydrate free base forms degraded rapidly under the test conditions. In addition, both the anhydrate and the hemihydrate free base degraded faster when exposed to hydrogen peroxide vapor at 30°C under dry condition than at 30°C/75% relative humidity (RH). A new degradation product was also observed under the drier condition. The proposed method provides more relevant screening conditions for solid dosage forms, and is useful in selecting optimal solid form(s), determining potential degradation products, and formulation screening during development.     

Characterization of pharmaceutical solids by scanning probe microscopy

The force-displacement profiles of four well-characterized materials that represent both soft/hard and plastic/brittle materials have been obtained using a novel nanoindentation technique. Flat surfaces of acetaminophen, potassium chloride, sucrose, and sodium stearate were prepared by melting or recrystallization, and the melting points were measured. Topographic and the corresponding first derivative images were obtained both before and after indentation. The materials were indented using a 10 s loading time, followed by a 2 s hold, and ending with a 10 s unloading time thereby providing a unique force-displacement profile for each material. The loading profile of acetaminophen was discontinuous, whereas the profiles for the other three materials were smooth. The profiles were analyzed and the rank order of hardness was sucrose > acetaminophen > KCl > sodium stearate, which is consistent with the literature. The rank order of the stiffness, which is related to the modulus of elasticity, was sucrose > KCl > acetaminophen > sodium stearate. Given the flexibility and power of this approach, nanoindentation coupled with atomic force microscopy may be a useful means to characterize materials for evaluating tablet-processing conditions, perhaps at a preformulation stage.     

Analytical techniques for quantification of amorphous/crystalline phases in pharmaceutical solids

The existence of different solid-state forms such as polymorphs, solvates, hydrates, and amorphous form in pharmaceutical drug substances and excipients, along with their downstream consequences in drug products and biological systems, is well documented. Out of these solid states, amorphous systems have attracted considerable attention of formulation scientists for their specific advantages, and their presence, either by accident or design is known to incorporate distinct properties in the drug product. Identification of different solid-state forms is crucial to anticipate changes in the performance of the material upon storage and/or handling. Quantitative analysis of physical state is imperative from the viewpoint of both the manufacturing and the regulatory control aimed at assuring safety and efficacy of drug products. Numerous analytical techniques have been reported for the quantification of amorphous/crystalline phase, and implicit in all quantitative options are issues of accuracy, precision, and suitability. These quantitative techniques mainly vary in the properties evaluated, thus yielding divergent values of crystallinity for a given sample. The present review provides a compilation of the theoretical and practical aspects of existing techniques, thereby facilitating the selection of an appropriate technique to accomplish various objectives of quantification of amorphous systems.     

Evaluating particle hardness of pharmaceutical solids using AFM nanoindentation

Understanding mechanical properties of pharmaceutical solids at the submicron scale can be very important to pharmaceutical research & development. In this paper, the hardness of individual particles of various pharmaceutical solids including sucrose, lactose, ascorbic acid, and ibuprofen was quantified using the atomic force microscopy (AFM) nanoindentation. Effects of data variation and indentation size or peak load on hardness are evaluated. The results show acceptable reproducibility and indicate that data variation may be primarily from the inhomogeneous nature of the samples. Different extents of indentation size or peak load effect on hardness were observed for the samples. With consideration of both data variation and indentation size effects, the hardness values of different samples were compared at similar contact depths or peak loads. The hardness ranked as: ascorbic acid>sucrose>lactose approximately ibuprofen, at contact depths from approximately 40 to 400nm or peak loads ranging from approximately 16 to 70muN. Additionally, the potential implication of particle hardness to compact hardness and tableting performance was discussed.     

One-phase crystal disorder in pharmaceutical solids and its implication for solid-state stability

Solid-state disorders of active pharmaceutical ingredients have been characterized by means of X-ray diffraction techniques and solid-state nuclear magnetic resonance spectroscopy. The results determined that the pleuromutilin-derivative, I, displays a unique continuous conformational disorder while retaining its long-range crystalline structure. The propionic acid (PA) version of this compound displayed partial crystalline order and site disorder of PA, depending on the quantity of PA incorporated in the structure. Thus, I is a unique example of one-phase crystalline–amorphous model. Physical and chemical stability data was acquired on these disordered systems and discussed in relation with the characterized disorder present in the crystal systems. Analysis of the results showed that in contrast to phase-separated amorphous, restrained disorders do not influence the stability.     

New challenges for pharmaceutical formulations and drug delivery systems characterization using isothermal titration calorimetry

Long viewed as the 'method of choice' for characterizing thermodynamics and stoichiometry of molecular interactions, with high sensitivity, isothermal titration calorimetry (ITC) has been applied to many areas of pharmaceutical analysis. This review highlights ITC employment to measure binding thermodynamics and their use for pharmaceutical formulations and drug delivery system characterization particularly cyclodextrin-guest interactions, investigation of micellar-based systems, polyelectrolytes, nucleic acid interactions with multivalent cations and the optimization of DNA targeting and delivery. Furthermore, the potential of ITC for the characterization of different functionalities carried by nanoparticles as well as their interaction with living systems was outlined.     

Measurement of process-dependent material properties of pharmaceutical solids by nanoindentation

The purpose of this work was to evaluate nanoindentation as a means to characterize the material properties of pharmaceutical solids. X-ray diffraction of potassium chloride and acetaminophen showed that samples prepared by cooling a melt to a crystalline sample as opposed to slow recrystallization had the same crystal structure. With analysis of the force-displacement curves, the KCl quenched samples had a hardness that was 10 times higher than the recrystallized KCl, while acetaminophen quenched samples were 25% harder than the recrystallized samples. The elastic moduli of the quenched samples were also much greater than that observed for the recrystallized samples. Although the elasticity was independent of load, the hardness increased with load for acetaminophen. With each sample, the flow at constant load increased with applied load. Etching patterns obtained by atomic force microscopy showed that the KCl quenched sample had a higher dislocation density than the recrystallized sample, although there was no evident difference in the acetaminophen samples. Overall, the differences in the observed sample properties may be related to the dislocation density. Thus, nanoindentation has been shown to be a sensitive method for determining a processed-induced change in the hardness, creep, and elasticity of KCl and acetaminophen.