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This book explains theoretical and technological aspects of amorphous drug formulations. It is intended for all those wishing to increase their knowledge in the field of amorphous pharmaceuticals. Conversion of crystalline material into the amorphous state, as described in this book, is a way to overcome limited water solubility of drug formulations, in this way enhancing the chemical activity and bioavailability inside the body. Written by experts from various fields and backgrounds, the book introduces to fundamental physical aspects (explaining differences between the ordered and the disordered solid states, the enhancement of solubility resulting from drugs amorphization, physical instability and how it can be overcome) as well as preparation and formulation procedures to produce and stabilize amorphous pharmaceuticals. Readers will thus gain a well-funded understanding and find a multi-faceted discussion of the properties and advantages of amorphous drugs and of the challenges in producing and stabilizing them. The book is an ideal source of information for researchers and students as well as professionals engaged in research and development of amorphous pharmaceutical products.
Providing a roadmap from early to late stages of drug development, this book overviews amorphous solid dispersion technology – a leading platform to deliver poorly water soluble drugs, a major hurdle in today’s pharmaceutical industry. • Helps readers understand amorphous solid dispersions and apply techniques to particular pharmaceutical systems • Covers physical and chemical properties, screening, scale-up, formulation, drug product manufacture, intellectual property, and regulatory considerations • Has an appendix with structure and property information for polymers commonly used in drug development and with marketed drugs developed using the amorphous sold dispersion approach • Addresses global regulatory issues including USA regulations, ICH guidelines, and patent concerns around the world
Providing a roadmap from early to late stages of drug development, this book overviews amorphous solid dispersion technology – a leading platform to deliver poorly water soluble drugs, a major hurdle in today’s pharmaceutical industry. • Helps readers understand amorphous solid dispersions and apply techniques to particular pharmaceutical systems • Covers physical and chemical properties, screening, scale-up, formulation, drug product manufacture, intellectual property, and regulatory considerations • Has an appendix with structure and property information for polymers commonly used in drug development and with marketed drugs developed using the amorphous sold dispersion approach • Addresses global regulatory issues including USA regulations, ICH guidelines, and patent concerns around the world
This volume offers a comprehensive guide on the theory and practice of amorphous solid dispersions (ASD) for handling challenges associated with poorly soluble drugs. In twenty-three inclusive chapters, the book examines thermodynamics and kinetics of the amorphous state and amorphous solid dispersions, ASD technologies, excipients for stabilizing amorphous solid dispersions such as polymers, and ASD manufacturing technologies, including spray drying, hot melt extrusion, fluid bed layering and solvent-controlled micro-precipitation technology (MBP). Each technology is illustrated by specific case studies. In addition, dedicated sections cover analytical tools and technologies for characterization of amorphous solid dispersions, the prediction of long-term stability, and the development of suitable dissolution methods and regulatory aspects. The book also highlights future technologies on the horizon, such as supercritical fluid processing, mesoporous silica, KinetiSol®, and the use of non-salt-forming organic acids and amino acids for the stabilization of amorphous systems. Amorphous Solid Dispersions: Theory and Practice is a valuable reference to pharmaceutical scientists interested in developing bioavailable and therapeutically effective formulations of poorly soluble molecules in order to advance these technologies and develop better medicines for the future.
Using clear and practical examples, Polymorphism of Pharmaceutical Solids, Second Edition presents a comprehensive examination of polymorphic behavior in pharmaceutical development that is ideal for pharmaceutical development scientists and graduate students in pharmaceutical science. This edition focuses on pharmaceutical aspects of polymorphism a
Poorly soluble crystalline drug candidates are often made amorphous to increase their solubility with the intent to enhance oral bioavailability, thus improving the likelihood of becoming a commercial drug product. Currently, considerable time, material and effort are expended to determine whether an amorphous approach will provide the required bioavailability improvement. However, often the solubility enhancement of the amorphous form is not fully realized in vivo due to solution-mediated phase transformation (SMPT). This study investigated the effects of key factors, through experimentation and modeling, that affect SMPT and model the potential effects of SMPT on bioavailability. Sparsely parameterized biopharmaceutical models were developed to quickly obtain estimates of the bioavailability from in vitro dissolution data for compounds that precipitate in the gastrointestinal tract. The models highlight the complex effects of drug absorption rate on expected in vivo drug peak concentration and duration in the small intestinal lumen from where orally administered drug is absorbed, depending on whether the peak concentration or the peak duration is assumed to better translate from in vitro to in vivo. Furthermore, a model with limited number of input variables allowed us to quantify variation in bioavailability based on known variations of one or more model input parameters. The differences in SMPT of a supersaturating system were compared in biorelevant media and a medium without surfactants. Amorphous spironolactone underwent SMPT to a channel hydrate in all three media which was confirmed by the decrease in dissolution rates assessed in a flow-through dissolution apparatus, as well as by the appearance of crystals on the amorphous solid surface detected by polarized light microscopy. Longer duration of supersaturation was found in both biorelevant media, compared to the medium without surfactants. The contribution(s) of the molecular mobility of the hydrated amorphous drug and degree of supersaturation to the rate of SMPT of amorphous spironolactone. The degree of supersaturation was not the sole determinant of SMPT. Rather, mobility of the solid at/near the dissolution surface of amorphous material, relative to 37°C (id est, physiological relevant temperature) is more likely to be govern the extent and time course of dissolution enhancement by amorphous drugs.
This volume is intended to provide the reader with a breadth of understanding regarding the many challenges faced with the formulation of poorly water-soluble drugs as well as in-depth knowledge in the critical areas of development with these compounds. Further, this book is designed to provide practical guidance for overcoming formulation challenges toward the end goal of improving drug therapies with poorly water-soluble drugs. Enhancing solubility via formulation intervention is a unique opportunity in which formulation scientists can enable drug therapies by creating viable medicines from seemingly undeliverable molecules. With the ever increasing number of poorly water-soluble compounds entering development, the role of the formulation scientist is growing in importance. Also, knowledge of the advanced analytical, formulation, and process technologies as well as specific regulatory considerations related to the formulation of these compounds is increasing in value. Ideally, this book will serve as a useful tool in the education of current and future generations of scientists, and in this context contribute toward providing patients with new and better medicines.
This authoritative volume provides a contemporary view on the latest research in molecules with optimal drug-like properties. It is a valuable source to access current best practices as well as new research techniques and strategies. Written by leading scientists in their fields, the text consists of fourteen chapters with an underlying theme of early collaborative opportunities between pharmaceutical and discovery sciences. The book explores the practical realities of performing physical pharmaceutical and biopharmaceutical research in the context of drug discovery with short timelines and low compound availability. Chapters cover strategies and tactics to enable discovery as well as predictive approaches to establish, understand and communicate risks in early development. It also examines the detection, characterization, and assessment of risks on the solid state properties of advanced discovery and early development candidates, highlighting the link between solid state properties and critical development parameters such as solubility and stability. Final chapters center on techniques to improve molecular solubilization and prevent precipitation, with particularly emphasis on linking physiochemical properties of molecules to formulation selection in preclinical and clinical settings.
Written by key experts in the field of nanomedicine, this book provides a broad introduction to the important field of nanomedicine and application of nanotechnology for drug delivery. It covers up-to-date information regarding various nanoparticulate drug delivery systems, describes the various opportunities for the application of nanoparticular drug carriers in different areas of clinical medicine, and analyzes already available information on their clinical applications. This book can be used as an advanced textbook by graduate students and young scientists and clinicians at the early stages of their career. It is also suitable for non-experts from related areas of chemistry, biochemistry, molecular biology, biomedical engineering, physiology, experimental and clinical medicine, and pharmaceutical sciences, who are interested in general problems of drug delivery and drug targeting, as well as in more specialized topics of using nanoparticulate-mediated drug delivery approaches in the individual areas of clinical medicine. Prof Torchilin is an expert in Nanomedicine and a recipient of numerous awards including the Lenin Prize in Science & Technology of the former USSR, membership in the European Academy of Sciences, and AAPS Research Achievement Award in Pharmaceutics and Drug Delivery. He served as an Associate Professor of Radiology at Harvard Medical School before joining Northeastern University as the Chairman of the Department of Pharmaceutical Sciences. Sample Chapter(s). Chapter 1: Introduction. Nanocarriers for Drug Delivery: Needs and Requirements (442 KB). Contents: Nanoparticle Flow: Implications for Drug Delivery (A T Florence); Polymer Micelles as Drug Carriers (E V Batrakova et al.); Lipoproteins as Pharmaceutical Carriers (S Liu et al.); Dendrimers as Nanoparticular Drug Carriers (S Svenson & D A Tomalia); Cells and Cell Ghosts as Drug Carriers (J M Lanao & M L Sayalero); Magnetic Nanoparticles as Drug Carriers (U O Hnfeli & M Chastellain); Liposomal Drug Carriers in Cancer Therapy (A A Gabizon); Delivery of Nanoparticles to the Cardiovascular System (B-A Khaw); Nanoparticles for Targeting Lymphatics (W Phillips); Nanoparticular Carriers for Ocular Drug Delivery (A Sanchez & M J Alonso); and other papers. Readership: Graduate students, academics in nanomedicine, clinicians, pharmacologists, pharmacists, bioengineers, researchers in biotechnology and diagnostic imaging."
The research described in this thesis is focused on increasing the dissolution properties of poorly water-soluble drugs using amorphous and drug-carrier systems. In this context attention was focused on understanding the complex molecular nature of amorphous forms and stabilising these forms with the use of carriers primarily by the application of solid dispersion technology. Two different carriers, polyvinylpyrrolidone (PVP) and silica were studied to determine their influence on the dissolution and stability enhancement of these drug-carrier systems. Preliminary studies were performed to understand the recrystallisation tendency of the amorphous form of a poorly water-soluble model drug, hydrocortisone prepared by different processing methods, spray drying and freeze drying. Amorphous forms were prepared from two solvent systems (96%v/v ethanol and 20%v/v ethanol) by spray drying and a 20%v/v ethanol solvent system by freeze drying. The recrystallisation tendency of hydrocortisone was evaluated by calculating configurational thermodynamic parameters (enthalpy, entropy and Gibbs free energy), relaxation data and kinetic parameters such as recrystallisation temperature and glass transition temperature. Accelerated stability studies were performed for one month at 40oC and 75% relative humidity. An attempt was made to relate the thermodynamic, kinetic and relaxation data to the stability data and the dissolution advantage observed for these amorphous forms. While kinetic data provided some indication of amorphous stability, configurational thermodynamic parameters and relaxation data did not relate to the actual stability behaviour for these systems studied. Results demonstrated the importance of carrying out real-time stability studies for amorphous drugs. The ability of PVP as a carrier to enhance the dissolution rate and stability of hydrocortisone was studied. Hydrocortisone:PVP solid dispersions were prepared by spray drying and freeze drying. Stability studies were performed to understand the influence of PVP on the stability of the prepared solid dispersions. Solid dispersions were prepared with varying weight fractions of PVP and its effect on the dissolution and stability was studied in detail. Finally, a comparison was made to establish the optimum method of preparation and carrier ratio which was effective in producing solid dispersions with enhanced dissolution rates and stability. It was concluded that solid dispersions with the highest weight fraction of PVP (75%w/w) prepared by freeze drying demonstrated the highest dissolution and greatest stability of all the solid dispersions prepared for this study. For further studies, a second model poorly water-soluble drug, sulfamethazine was selected. The effect of solvent system (40%v/v acetone and 50% tert-butyl alcohol) on the physicochemical properties of spray dried and freeze dried sulfamethazine was explored. Freeze dried drug from a 40%v/v acetone solution resulted in sulfamethazine with higher amorphous content with enhanced stability properties compared to other processed sulfamethazine forms. Although PVP was effective in producing amorphous dispersions with good dissolution properties, it was unable to inhibit recrystallisation resulting in decreased dissolution rates after storage at 40oC and 75% relative humidity. A primary reason for the inability of PVP to stabilise drug amorphous forms was attributed to its hygroscopic nature. Therefore, an alternative carrier, silica, was investigated for its potential to prepare drug-carrier system with enhanced dissolution and stability. Silica was selected because of its relatively lower hygroscopicity compared to PVP, its hydrophilicity and its extensive surface area. Two different types of silica were studied, porous (SBA15) and non-porous (Aerosil). The dissolution and stability properties of silica physical mixtures with spray dried and freeze dried sulfamethazine and control physical mixtures with unprocessed sulfamethazine were evaluated. Accelerated stability studies were performed to examine the effect of humidity and temperature on the dissolution behaviour of these drug-silica physical mixtures. Physical mixtures of processed sulfamethazine with aerosil showed greater increase in dissolution rates than the corresponding physical mixtures with SBA15. A conventional spray drying and a novel supercritical fluid processing method were investigated to prepare solid dispersions of sulfamethazine with SBA15 and Aerosil. The stability of these solid dispersions was studied in relation to the physical mixtures described earlier. It was found that spray drying using acetone solutions was not an effective method for the preparation of silica based solid dispersions of sulfamethazine with enhanced dissolution properties. The SCF processing method produced solid dispersions with enhanced dissolution rates. In contrast to hydrocortisone-PVP solid dispersions, sulfamethazine-silica physical mixtures and solid dispersions retained and in fact increased the dissolution rate of drug after stability studies. Compared to PVP, silica was effective as a carrier to produce drug-carrier systems with increased dissolution and stability. The dissolution behaviour of silica dispersions showed some evidence of controlled release for both porous and non-porous silica. Further studies are require to understand the relationship between processing parameters and drug-silica interactions, prior to exploiting silica as a carrier to produce solid dispersions with optimum dissolution and stability for commercial products.