Control And Prediction Of Solid State Of Pharmaceuticals

This thesis investigates a range of experimental and computational approaches for the discovery of solid forms. Furthermore, we gain, as readers, a better understanding of the key factors underpinning solid-structure and diversity. A major part of this thesis highlights experimental work carried out on two structurally very similar compounds. Another important section involves looking at the influence of small changes in structure and substituents on solid-structure and diversity using computational tools including crystal structure prediction, PIXEL calculations, Xpac, Mercury and statistical modeling tools. In addition, the author presents a fast validated method for solid-state form screening using Raman microscopy on multi-well plates to explore the experimental crystallization space. This thesis illustrates an inexpensive, practical and accurate way to predict the crystallizability of organic compounds based on molecular structure alone, and additionally highlights the molecular factors that inhibit or promote crystallization.

This thesis illustrates techniques for discovery of solid-state forms and probing the relationship between molecular structure and crystallisability. Also, the value of combined experimental and computational approaches to provide better understanding of the key factors underpinning the structural diversity in two groups each comprising of two structurally related pharmaceutical compounds is demonstrated. An effective methodology of high throughput crystallisation and analysis for polymorph, solvate and salt screening using quartz 96/48 multi well plate with an automated system for collecting high quality Raman spectra was developed and validated. Using this efficient technique, 10 novel salts of amoxapine, 3 novel physical forms of clozapine and 16 novel solid forms of olanzapine were obtained by utilising a total of only ~640 mgs of API and ~65 ml of solvents. A statistical model with ~70% prediction accuracy has been built for predicting the crystallisability of small organic molecules. This model is first of its type and provides an opportunity to identify problematic systems at early stages and would allow early targeting for improvements. Structurally related molecules within each group were found to have markedly different experimental solid-state diversity after comprehensive physical form screening using multiple crystallisation techniques selected to maximise the crystallisation search space. Crystal structure prediction studies have been proved to be an important tool in rationalisation of the observed solid-state diversity. PIXEL calculations revealed that the largest contribution to crystal stabilisation comes from dispersion energy and enabled the identification of dominant intermolecular interactions in the crystal structures. Structural packing analysis using XPac and Mercury has enabled the structural relationship amongst all the crystal structures to be investigated. In case of olanzapine solvates XPac analysis provides a rationale of desolvation products by highlighting the close relationships between the forms and desolvated 'end product'. Statistical modelling analysis revealed that the physicochemical properties of the solvents were directing the crystal packing in olanzapine solvates.

The field of solid state characterization is central to the pharmaceutical industry, as drug products are, in an overwhelming number of cases, produced as solid materials. Selection of the optimum solid form is a critical aspect of the development of pharmaceutical compounds, due to their ability to exist in more than one form or crystal structure (polymorphism). These polymorphs exhibit different physical properties which can affect their biopharmaceutical properties. This book provides an up-to-date review of the current techniques used to characterize pharmaceutical solids. Ensuring balanced, practical coverage with industrial relevance, it covers a range of key applications in the field. The following topics are included: Physical properties and processes Thermodynamics Intellectual guidance X-ray diffraction Spectroscopy Microscopy Particle sizing Mechanical properties Vapour sorption Thermal analysis & Calorimetry Polymorph prediction Form selection

Solid State Development and Processing of Pharmaceutical Molecules A guide to the lastest industry principles for optimizing the production of solid state active pharmaceutical ingredients Solid State Development and Processing of Pharmaceutical Molecules is an authoritative guide that covers the entire pharmaceutical value chain. The authors—noted experts on the topic—examine the importance of the solid state form of chemical and biological drugs and review the development, production, quality control, formulation, and stability of medicines. The book explores the most recent trends in the digitization and automation of the pharmaceutical production processes that reflect the need for consistent high quality. It also includes information on relevant regulatory and intellectual property considerations. This resource is aimed at professionals in the pharmaceutical industry and offers an in-depth examination of the commercially relevant issues facing developers, producers and distributors of drug substances. This important book: Provides a guide for the effective development of solid drug forms Compares different characterization methods for solid state APIs Offers a resource for understanding efficient production methods for solid state forms of chemical and biological drugs Includes information on automation, process control, and machine learning as an integral part of the development and production workflows Covers in detail the regulatory and quality control aspects of drug development Written for medicinal chemists, pharmaceutical industry professionals, pharma engineers, solid state chemists, chemical engineers, Solid State Development and Processing of Pharmaceutical Molecules reviews information on the solid state of active pharmaceutical ingredients for their efficient development and production.

"Polymorphism in the Pharmaceutical Industry - Solid Form and Drug Development" highlights the relevance of polymorphism in modern pharmaceutical chemistry, with a focus on quality by design (QbD) concepts. It covers all important issues by way of case studies, ranging from properties and crystallization, via thermodynamics, analytics and theoretical modelling right up to patent issues. As such, the book underscores the importance of solid-state chemistry within chemical and pharmaceutical development. It emphasizes why solid-state issues are important, the approaches needed to avoid problems and the opportunities offered by solid-state properties. The authors include true polymorphs as well as solvates and hydrates, while providing information on physicochemical properties, crystallization thermodynamics, quantum-mechanical modelling, and up-scaling. Important analytical tools to characterize solid-state forms and to quantify mixtures are summarized, and case studies on solid-state development processes in industry are also provided. Written by acknowledged experts in the field, this is a high-quality reference for researchers, project managers and quality assurance managers in pharmaceutical, agrochemical and fine chemical companies as well as for academics and newcomers to organic solid-state chemistry.

Presents a detailed discussion of important solid-state properties, methods, and applications of solid-state analysis Illustrates the various phases or forms that solids can assume and discussesvarious issues related to the relative stability of solid forms and tendencies to undergo transformation Covers key methods of solid state analysis including X-ray powder diffraction, thermal analysis, microscopy, spectroscopy, and solid state NMR Reviews critical physical attributes of pharmaceutical materials, mainly related to drug substances, including particle size/surface area, hygroscopicity, mechanical properties, solubility, and physical and chemical stability Showcases the application of solid state material science in rational selection of drug solid forms, analysis of various solid forms within drug substance and the drug product, and pharmaceutical product development Introduces appropriate manufacturing and control procedures using Quality by Design, and other strategies that lead to safe and effective products with a minimum of resources and time

This book is the first to combine computational material science and modeling of molecular solid states for pharmaceutical industry applications. • Provides descriptive and applied state-of-the-art computational approaches and workflows to guide pharmaceutical solid state chemistry experiments and to support/troubleshoot API solid state selection • Includes real industrial case examples related to application of modeling methods in problem solving • Useful as a supplementary reference/text for undergraduate, graduate and postgraduate students in computational chemistry, pharmaceutical and biotech sciences, and materials science