Generation of High Drug Loading Amorphous Solid Dispersions by Different Manufacturing Processes

Generation of High Drug Loading Amorphous Solid Dispersions by Different Manufacturing Processes
Author: Bhianca Lins de Azevedo Costa
Publisher:
Total Pages: 252
Release: 2018
Genre:
ISBN:
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The main difficulty when an Active Pharmaceutical Ingredient (API) is orally administered is to guarantee that the clinical dose of the API will be dissolved in the available volume of gastrointestinal fluids. However, about 40% of APIs with market approval and nearly 90% of molecules in the discovery pipeline are poorly water-soluble and exhibits a poor oral absorption, which leads to a weak bioavailability. Amorphous solid dispersions (ASD) are considered as one of the most effective strategies to solve solubility limitations of poorly-water soluble compounds and hence, enhance their oral bioavailability. Despite their introduction as technical strategy to enhance oral APIs bioavailability more than 50 years ago, ASD formation and physical stability remains a subject of intense research. Indeed, several factors can influence the physical storage stability of ASD, among them, the glass transition temperature of the API-carrier binary mixture, the apparent solubility of the API in the carrier, interactions between API and carrier, and the manufacturing process. This thesis consisted of two parts that aim on developing new formulations of ASD of an antiretroviral API, Efavirenz (EFV), dispersed in an amphiphilic polymer, Soluplus, by using two different processes, Spray-drying (SD) and Hot-melt extrusion (HME). EFV is the class II BCS API of our choice because it is a challenging API for new formulations. It needs higher-dosed ASDs, for which chemical and physical stability during storage and dissolution will be critical. Aiming a rational development of high-loaded EFV-Soluplus ASDs, the first part focused on the construction of a temperature- composition EFV-Soluplus phase diagram. The phase-diagram was constructed from a thermal study of recrystallization of a supersaturated ASD (85 wt% in EFV), generated by spray drying. To our knowledge, this is the first study reporting a phase-diagram for this binary system. This phase-diagram is very useful and demonstrated that the EFV solubility in Soluplus ranges from 20 wt% (25 °C) to 30 wt% (40 °C). ASD of EFV in Soluplus containing more than 30 wt% of EFV should be monitored over storage under typical temperature conditions. This phase-diagram might be considered as a preformulation tool for researchers studying novel ASD of EFV in Soluplus, to predict (thermodynamic and kinetic) stability. ASD prepared by different techniques can display differences in their physicochemical properties. The second part of this thesis focused on the manufacturing of ASD by HME or SD processes. This study clearly shows that ASD is a useful formulation strategy to improve the aqueous solubility and the dissolution rate of EFV from EFV-Soluplus binary mixtures. HME and SD manufacturing processes demonstrated to be efficient to generate ASDs in a large range of compositions and loads of EFV. The optimization of EFV to Soluplus ratio can be used to tailor the release kinetics from ASD. The choice of a high EFV load exceeding the thermodynamic solid solubility in Soluplus is possible but it needs the consideration of its kinetic stability over time.

Amorphous Solid Dispersions

Amorphous Solid Dispersions
Author: Navnit Shah
Publisher: Springer
Total Pages: 702
Release: 2014-11-21
Genre: Medical
ISBN: 1493915983
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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.

Processing Impact on the Performance of Amorphous Solid Dispersions

Processing Impact on the Performance of Amorphous Solid Dispersions
Author: Abbe Jeanne Haser
Publisher:
Total Pages: 582
Release: 2017
Genre:
ISBN:
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The level of understanding of amorphous solid dispersions has grown significantly in the last two decades. A number of commercial amorphous solid dispersions have been approved and they have become the industry norm for overcoming poor water-solubility when an enabling technology is necessary. Despite their success, there are still challenges in developing high performing amorphous solid dispersions. The impact of processing technique on the quality of the resultant amorphous solid dispersion is an area that is not well understood. Spray drying and melt extrusion are the two dominant manufacturing techniques for preparing amorphous solid dispersions. The mechanism for the formation of an amorphous solid dispersion from each process is very different. Therefore, the resulting material can have different properties which contribute to the overall performance of the amorphous solid dispersions. A better understanding of processing impact is necessary. Another challenge in the development of amorphous solid dispersions is the limitation to process high melting point drug substances that also have limited organic solvent solubility. For these substances, spray drying cannot be used, and at the high temperatures required to dissolve the drug in the polymer carrier, there is significant degradation during melt extrusion. Strategies such as plasticizer, supercritical fluids, and polymer selection for melting point suppression have been used in the past but have limitations. This research focuses on the impact of the processing technique on the physical and chemical stability of the resultant amorphous solid dispersions as well as the resultant dissolution performance. This work showed that based on its mechanism of formation, melt extrusion can have an advantage when preparing a high potency amorphous solid dispersion with a fast crystallizing drug. Due to the high level of mixing in the extruder and higher temperature, a more homogeneous and thermodynamically stable amorphous solid dispersion can be prepared. Spray drying, in contrast, can produce a higher drug loading amorphous solid dispersion, however, the material is less homogeneous and physically unstable. Additionally, through process and formulation understanding, a previously deemed “un-extrudable” drug substance was successfully processed by melt extrusion. This process was also successfully scaled from lab to pilot scale equipment.

Hot-Melt Extrusion

Hot-Melt Extrusion
Author: Dennis Douroumis
Publisher: John Wiley & Sons
Total Pages: 404
Release: 2012-04-24
Genre: Science
ISBN: 1118307879
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Hot-melt extrusion (HME) - melting a substance and forcing it through an orifice under controlled conditions to form a new material - is an emerging processing technology in the pharmaceutical industry for the preparation of various dosage forms and drug delivery systems, for example granules and sustained release tablets. Hot-Melt Extrusion: Pharmaceutical Applications covers the main instrumentation, operation principles and theoretical background of HME. It then focuses on HME drug delivery systems, dosage forms and clinical studies (including pharmacokinetics and bioavailability) of HME products. Finally, the book includes some recent and novel HME applications, scale -up considerations and regulatory issues. Topics covered include: principles and die design of single screw extrusion twin screw extrusion techniques and practices in the laboratory and on production scale HME developments for the pharmaceutical industry solubility parameters for prediction of drug/polymer miscibility in HME formulations the influence of plasticizers in HME applications of polymethacrylate polymers in HME HME of ethylcellulose, hypromellose, and polyethylene oxide bioadhesion properties of polymeric films produced by HME taste masking using HME clinical studies, bioavailability and pharmacokinetics of HME products injection moulding and HME processing for pharmaceutical materials laminar dispersive & distributive mixing with dissolution and applications to HME technological considerations related to scale-up of HME processes devices and implant systems by HME an FDA perspective on HME product and process understanding improved process understanding and control of an HME process with near-infrared spectroscopy Hot-Melt Extrusion: Pharmaceutical Applications is an essential multidisciplinary guide to the emerging pharmaceutical uses of this processing technology for researchers in academia and industry working in drug formulation and delivery, pharmaceutical engineering and processing, and polymers and materials science. This is the first book from our brand new series Advances in Pharmaceutical Technology. Find out more about the series here.

Pharmaceutical Technologies for Improving Drug Loading in the Formulation of Solid Dispersions

Pharmaceutical Technologies for Improving Drug Loading in the Formulation of Solid Dispersions
Author: Kevin Patrick O'Donnell
Publisher:
Total Pages: 682
Release: 2011
Genre:
ISBN:
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It is estimated that 90% of new chemical entities in development pipelines exhibit poor aqueous solubility. For compounds not limited by biological membrane permeability, this poor aqueous solubility is the limiting factor in bioavailability. Therefore, the formulation of such drugs has primarily been centered on improving dissolution properties. Traditional approaches for overcoming poor aqueous solubility include salt formation of the active ingredient, complexation, the use of surface active agents, formulation into oil based systems, particle size reduction, or a combination of these methods. More recently amorphous solid dispersions have been explored. Currently, the drug loading within solid dispersions is limited resulting in large quantities of the formulation being required for a therapeutically relevant dose. In the frame of the work herein, Thin Film Freezing was utilized to generate high drug loaded amorphous solid dispersions of the poorly water soluble drug phenytoin utilizing a hydrophilic polymer or an amphiphilic graft copolymer for system stabilization. Additionally a new solvent removal technique, atmospheric freeze drying, was investigated for removal of the solvents used during Thin Film Freezing. The Thin Film Freezing materials were subsequently incorporated into a polymeric carrier for solid dispersion formulation by a novel fusion production technique termed Kinetisol® dispersing. Studies of the solid dispersions produced by Thin Film Freezing revealed an amorphous system had been obtained for both stabilizing polymers. The formulation containing a hydrophilic carrier was capable of achieving supersaturation. Conversely, the amphiphilic graft copolymer demonstrated a phenytoin-polymer interaction resulting in poor dissolution. Atmospheric freeze drying of the Thin Film Freezing product demonstrated that the alternative drying technique generated powders with significantly improved handling properties as a result of reduced electrostatic interactions due to the increased pore size, reduced surface area, larger particle size, and higher, though acceptable, residual solvent levels. The use of Thin Film Freezing powders during Kinetisol Dispersing resulted in a single phase amorphous system while solid dispersions produced from physical mixtures of bulk materials were amorphous two-phase systems. This indicates that the use of amorphous drug compositions during solid dispersion production may increase drug loading in the final system while remaining single phase in nature.

Pharmaceutical Amorphous Solid Dispersions

Pharmaceutical Amorphous Solid Dispersions
Author: Ann Newman
Publisher: John Wiley & Sons
Total Pages: 502
Release: 2015-03-09
Genre: Science
ISBN: 1118455207
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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

Melt Extrusion

Melt Extrusion
Author: Michael A. Repka
Publisher: Springer Science & Business Media
Total Pages: 472
Release: 2013-10-11
Genre: Medical
ISBN: 1461484324
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This volume provides readers with the basic principles and fundamentals of extrusion technology and a detailed description of the practical applications of a variety of extrusion processes, including various pharma grade extruders. In addition, the downstream production of films, pellets and tablets, for example, for oral and other delivery routes, are presented and discussed utilizing melt extrusion. This book is the first of its kind that discusses extensively the well-developed science of extrusion technology as applied to pharmaceutical drug product development and manufacturing. By covering a wide range of relevant topics, the text brings together all technical information necessary to develop and market pharmaceutical dosage forms that meet current quality and regulatory requirements. As extrusion technology continues to be refined further, usage of extruder systems and the array of applications will continue to expand, but the core technologies will remain the same.

Solubility enhancement of poorly water-soluble drugs by solid dispersion

Solubility enhancement of poorly water-soluble drugs by solid dispersion
Author: Adela Kalivoda
Publisher: Cuvillier Verlag
Total Pages: 198
Release: 2012-06-25
Genre: Medical
ISBN: 3736941412
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Summary Solid dispersions are a promising approach for controlled release drug delivery systems as both the bioavailability enhancement of poorly water-soluble drugs as well as the sustained release of water-soluble drugs are possible to optimize their in vivo performance. Different methods for the manufacture of solid dispersion systems have been introduced in literature. In the present work, two methods are compared: hot-melt extrusion and ultrasound-assisted compaction technique. Various carrier systems and drugs with different physicochemical properties are applied to investigate the feasibility of the technologies for pharmaceutical formulation. The formulations are compared to the corresponding untreated physical blends of the components regarding their solid state structure and dissolution behavior to assess the effect of the manufacturing technique. Ultrasound-assisted compaction technique improves the initial dissolution rate of fenofibrate, a poorly water-soluble model drug. The crystalline API is partially converted into its amorphous state. As equivalent results can be achieved if the polymers are added directly to the dissolution medium, the dissolution enhancement is attributed to an improved wettability of the drug. A statistical design of experiments is employed to investigate the effect of the process parameters on the results. Difficulties are encountered in the determination of process parameters which result in an optimal outcome. The process is very sensitive to the smallest changes of settings, for example of the position of the sonotrode. Additionally, the delivery of ultrasound energy is inhomogeneous. There is no or only insufficient user control of these parameters available. Furthermore, the duration of ultrasound energy delivery which is identified as a crucial parameter cannot be set by the user. The variable factors ultrasound energy, pressure of the lower piston and pressure of the upper piston affect the defined responses in the opposite direction. Hence, there are no settings which result in a satisfactory outcome. A strong influence of the material characteristics on the process is observed leading to a batch to batch variability. Due to an insufficient reproducibility of results, the application of the technology cannot be recommended in its current state in the pharmaceutical formulation development and/or production. Improvements in homogeneity of energy delivery, process monitoring, user control and amount of leakage are mandatory for an acceptable performance and a future application in the pharmaceutical sector. The polymers COP, HPMC and PVCL-PVAc-PEG are well suitable as carriers for hot-melt extruded formulations of fenofibrate. All three extrudates are amorphous one-phase systems with the drug molecularly dispersed in the polymer. The enhancement of the initial dissolution rate and the maximum concentration level achieved are dependent on the applied carrier system. Supersaturation levels of up to 12.1 times are reached which are not stable due to recrystallization processes. The application of blends of polymers as carriers reduces the decrease rate after cmax. Because of water absorption and polymer relaxation, the overall dissolution performance decreases with increasing storage times which can be avoided through an optimization of the packaging. If oxeglitazar is used as API, the initial dissolution rate of the extrudates is below that of the untreated drug, with the exception of the ternary blend of COP, HPMC and oxeglitazar which shows a substance-specific super-additive effect. In contrast to the other extrudates, the formulation of PVCL-PVAc-PEG and oxeglitazar does not form a molecularly dispersed solid solution of the drug in the carrier. Instead, an amorphous two-phase system is present. No changes are observed after storage, presumably due to higher glass transition temperatures of the hot-melt extruded systems which are considerably above those of the corresponding fenofibrate extrudates. With felodipine as API, the dissolution profile is enhanced with COP as single carrier. If HPMC or PVCL-PVAc-PEG is used as single or additional polymeric carriers, the dissolution is equivalent (HPMC) or lower (PVCL-PVAc-PEG) than that of the pure drug although molecularly disperse systems are present in all cases. Out of the two investigated methods only hot-melt extrusion is a suitable technology to manufacture solid dispersions with an improved dissolution behavior. The dissolution profile of the extrudates can be influenced by adding polymers with differing physicochemical characteristics. Predictions on the dissolution behavior of the extrudates with polymeric blends as carriers can be made if there is knowledge on the dissolution profiles of the corresponding single polymeric extrudates. Due to substance-specific effects, the results are not transferable from drug to drug. Even so, the data are promising as the release behavior of the manufactured extrudates can be easily modified and readily adapted to one's needs. Further research will have to be conducted to verify the concept and the relevance of the results in vivo. Zusammenfassung Feste Dispersionen sind ein vielversprechender Ansatz zur Herstellung von Drug Delivery-Systemen mit kontrollierter Wirkstofffreisetzung, da sie sowohl die Bioverfügbarkeit schlecht wasserlöslicher Arzneistoffe verbessern als auch die Freisetzung gut wasserlöslicher Arzneistoffe verzögern können und so deren in vivo Verhalten optimieren. Verschiedene Herstellungsmethoden wurden in der Literatur vorgestellt. In der vorliegenden Arbeit werden zwei Technologien miteinander verglichen: Schmelzextrusion und Ultraschall gestützte Verpressung (USAC). Verschiedene Trägersysteme und Arzneistoffe mit unterschiedlichen physikochemischen Eigenschaften werden untersucht, um die Einsatzmöglichkeit im pharmazeutischen Bereich zu überprüfen. Die Struktur der hergestellten Systeme und deren Freisetzungsverhalten werden mit den physikalischen Mischungen der Komponenten verglichen, um den Einfluss der Formulierung zu bestimmen. Durch USAC wird die initiale Freisetzungsrate von Fenofibrat, einem schlecht wasserlöslichen Modellarzneistoff, verbessert. Eine teilweise Umwandlung vom kristallinen in den amorphen Zustand tritt auf. Vergleichbare Ergebnisse werden bei einer Polymerzugabe zum Freisetzungsmedium erreicht; daher wird davon ausgegangen, dass vor allem eine verbesserte Benetzbarkeit des Arzneistoffs eine Rolle spielt. Mittels statistischer Versuchsplanung wird der Einfluss der verschiedenen Prozessparameter untersucht. Die Einstellung der Prozessparameter, um ein optimales Ergebnis zu erhalten, gestaltet sich schwierig. Der Prozess reagiert auf kleinste Veränderungen, zum Beispiel der Position der Sonotrode, überaus sensitiv. Außerdem wird die Ultraschallenergie nicht homogen übertragen. Die Kontrolle dieser Parameter durch den Anwender ist nicht oder nur unzureichend möglich. Ebenso kann die Dauer der Ultraschallapplizierung, die essentiell für den Prozess ist, nicht eingestellt werden. Die Prozessparameter Ultraschallenergie, Unterstempeldruck und Sonotrodendruck beeinflussen die Zielgrößen in entgegengesetzter Richtung. Daher gibt es keine Einstellung, die für alle Zielgrößen optimale Ergebnisse liefert. Zusätzlich ist der Prozess stark abhängig von den Eigenschaften des verwendeten Materials: Die Verwendung unterschiedlicher Polymerchargen macht eine Anpassung der Prozessparameter notwendig, um vergleichbare Ergebnisse zu erhalten. Eine ausreichende Reproduzierbarkeit der Ergebnisse für einen Einsatz dieser Technologie in Formulierungsentwicklung oder Produktion ist nicht gegeben. Eine homogene Ultraschallenergiezufuhr sowie Verbesserungen der Prozessüberwachung, der Benutzerkontrolle und eine Verminderung der austretenden Materialmenge sind für eine akzeptable Leistung und eine zukünftige Anwendung im pharmazeutischen Bereich zwingend erforderlich. Die Polymere COP, HPMC, PVCL-PVAc-PEG sind für eine Freisetzungsverbesserung von Fenofibrat mittels Schmelzextrusion geeignet. Es liegen einphasige, molekulardisperse feste Lösungen vor. Abhängig von der Trägersubstanz wird die initiale Freisetzungsrate unterschiedlich stark erhöht, ebenso die maximale Konzentration des Arzneistoffes in Lösung. Eine bis zu 12.1-fache Übersättigung wird erreicht, die aufgrund von Rekristallisationsprozessen nicht stabil ist. Der Einsatz von polymeren Mischungen reduziert die Geschwindigkeit des Konzentrationsabfalls. Die Absorption von Wasser und Relaxationseffekte vermindern die Freisetzungserhöhung mit zunehmender Lagerdauer; dieser Entwicklung kann durch eine Optimierung des Packmittels entgegengewirkt werden. Wird der ebenfalls schwer wasserlösliche Arzneistoff Oxeglitazar verwendet, so ist die initiale Freisetzungsrate der Extrudate der des reinen Arzneistoffs unterlegen, mit Ausnahme der ternären Mischung von COP, HPMC und Oxeglitazar, die einen substanzspezifischen überadditiven Effekt aufweist. PVCL-PVAc-PEG-Oxeglitazar-Extrudate bilden im Gegensatz zu den übrigen Formulierungen keine molekulardisperse feste Lösung, sondern ein amorphes Zwei-Phasen-System. Eine Veränderung während der Lagerzeit wird nicht beobachtet, vermutlich aufgrund der höheren Glasübergangstemperaturen dieser Systeme. Lediglich das Freisetzungsprofil von COP-Felodipin-Extrudaten ist verbessert. Gegenüber dem reinen Arzneistoff ist die Freisetzung der übrigen Extrudate vergleichbar (HPMC) oder verringert (PVCL-PVAc-PEG), obwohl auch hier molekulardisperse Systeme vorliegen. Von den beiden untersuchten Technologien ist lediglich die Schmelzextrusion geeignet, um feste Dispersionen mit einem verbesserten Freisetzungsverhalten herzustellen. Das Freisetzungsprofil der Extrudate kann durch den Zusatz von Polymeren mit unterschiedlichen Eigenschaften optimiert und vorhergesagt werden, wenn das Freisetzungsprofil der Einzelpolymer-Extrudate bekannt ist. Die Ergebnisse sind aufgrund von substanzspezifischen Effekten nicht von Arzneistoff auf Arzneistoff übertragbar. Nichtsdestotrotz sind die Erkenntnisse dieser Arbeit vielversprechend, da gezeigt wird, dass das Freisetzungsprofil der Extrudate leicht beeinflusst und an spezifische Anforderungen angepasst werden kann. Weitere Untersuchungen sind notwendig, um das Konzept und die Relevanz der Ergebnisse in vivo zu überprüfen.

Preparation and Characterization of Carvedilol and Indomethacin Amorphous Solid Dispersions

Preparation and Characterization of Carvedilol and Indomethacin Amorphous Solid Dispersions
Author: Alena Duszová
Publisher:
Total Pages: 148
Release: 2019
Genre:
ISBN:
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Amorphous solid dispersions provide one of the few approaches available for improving the solubility of poorly water-soluble active pharmaceutical ingredients. They are mainly 2-component systems consisting of drug and polymer, where the amorphous drug is molecularly dispersed in an amorphous polymer matrix. The presence of polymer helps to maintain the drug in an amorphous state, which is thermodynamically unstable due to the possession of excess Gibbs free energy, enthalpy and entropy. To delay or prevent crystallization, the molecular mobility of the amorphous glass should be sufficiently low to avoid nuclei formation and crystal growth and is achieved by the maintaining the amorphous solid dispersion at a specific storage temperature and conditions, together with strong drug-polymer interactions. One of the major preparation processes for amorphous solid dispersions involves hot melt extrusion, producing solid dispersions at elevated temperatures without solvents. Four amorphous solid dispersions of 20% and 40% (w/w) carvedilol and indomethacin were manufactured using HPMC-AS as a polymeric carrier. Solid dispersions were characterized as freshly manufactured powders, as they were during a 1-month stability study using various analytical methods. Attention was paid to the molecular interactions in solid dispersions, miscibility, phase separation, crystallinity and molecular mobility. Solid dispersions of carvedilol exhibited satisfactory stability, which was reflected in preservation of amorphous carvedilol due to the sufficiently high glass transition temperature of the solid dispersions and the drug-polymer interactions. Indomethacin solid dispersions demonstrated the importance of drug loading in solid dispersions, together with the moderate or weak intermolecular interactions between drug and polymer. The enthalpy relaxation provides information regarding the lower molecular mobility of carvedilol in solid dispersions, indicating sufficient stabilization of amorphous drug by the selected polymer. Moreover, the intermolecular interactions were studied below and higher than the glass transition of the mixtures with different drug loadings, using temperature-dependent infrared spectroscopy. During this experiment, it was found that the intermolecular hydrogen bonds varied with the composition and measured temperature, resulting in disruption of intermolecular hydrogen bonds after passing the glass transition temperature.

Processing Challenging Active Pharmaceutical Ingredients and Polymers by Kinetisol to Produce Amorphous Solid Dispersions with Improved In-vitro and In-vivo Performance

Processing Challenging Active Pharmaceutical Ingredients and Polymers by Kinetisol to Produce Amorphous Solid Dispersions with Improved In-vitro and In-vivo Performance
Author: Daniel James Ellenberger
Publisher:
Total Pages: 494
Release: 2017
Genre:
ISBN:
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KinetiSol processing is an emerging technology for processing amorphous solid dispersions for pharmaceutical delivery of poorly water soluble drugs. Chapter 1 reviews the current literate around the application of this technology and provides insights into its benefits to pharmaceutical product development for poorly water soluble drugs. In Chapter 2, KinetiSol processing was used to render amorphous the poorly water soluble drug vemurafenib. Vemurafenib was challenging because conventional processes of pharmaceutical amorphous dispersions (hot melt extrusion and spray drying) were unable to render formulations containing this molecule amorphous and a non-ideal solvent-controlled coprecipitation process was utilized in production of its commercial product. Material generated by the KinetiSol process had particle morphology that differentiated it from the commercial particles. In-vitro and in-vivo performance analysis of the KinetiSol and commercial materials demonstrated enhanced product performance and drug exposure for the materials processed by KinetiSol. In Chapter 3, KinetiSol processing produced a high drug load formulation of the anti-viral and pharmacokinetic boosting drug, ritonavir. The amorphous solid dispersion of ritonavir was demonstrated as amorphous and intimately mixed by sensitive analysis such as solid state nuclear magnetic resonance. During comparison to the commercial product for ritonavir, transmembrane flux analysis revealed similar permeation rates for both dosages. Subsequent in-vivo pharmacokinetic analysis in dogs resulted in equivalent exposure for the test and reference products with a small reduction in maximum plasma concentration. It was concluded that the tablet generated in the study could serve as a pharmacokinetic booster with tablet mass reduced by approximately half. In Chapter 4, the extent of a surprising pharmacokinetic result with a lubricant was investigated. The result was surprising as lubricants such as magnesium stearate are typically understood to hinder performance in dosage forms containing poorly soluble drugs and are typically avoided, but the original result showed a significant increase in exposure. The study evaluated several additional cases and demonstrated positive effects of lubricant inclusion for weak acid, neutral, and weak base example compounds. Additionally, the study evaluated additional components not classified as pharmaceutical lubricants but with similar physiochemical properties to magnesium stearate and demonstrated similar positive benefits for these additional compounds