By understanding crystallization processes and choosing the right process parameters, it is possib. I mentioned polymorphs the other day, and no mention of those should go by without a reference to the classic 1995 article on disappearing polymorphs and its 2015 followup. Polymorphism is the phenomenon that a chemical substance crystallizes in more than one crystal structure with different arrangements andor conformations of the molecules in the crystal lattice. Optimization and scaleup of crystallization and precipitation to produce a product that consistently meets purity, yield, form and particle size specifications can be one of the biggest challenges of process development.
Thermochemistry and conformational polymorphism of a. 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. Crystalline forms were studied by various solidstate analytical. Thin films of glycine and acetaminophen were obtained using a simple flow coating. The process is especially important for manufacturing apis 1522. Crystal polymorphism in chemical process development, annual.
Polymorphism materials science in materials science, polymorphism is the ability of a solid material to exist in more than one form or crystal structure. Based on the authors handson experiences as process engineers at merck, crystallization of organic compounds guides readers through the practical aspects of crystallization. Crystal polymorphism of sodium benzene1,3 dicarboxy5sulfonate monohydrate. Because the water molecule is small and able to form hydrogen bonds, it is easily incorporated into the. Polymorphism is quite common for the same material to crystallize in different more than one arrangement of molecules in crystal.
The occurrence of crystals of the same molecule, but of different polymorphic form, with the same crystal habit poses limitations for the. Polymorphism is a common phenomenon of crystalline materials. A read is counted each time someone views a publication summary such as the title, abstract, and list of authors, clicks on a figure, or views or downloads the fulltext. Physicochemical properties of api impact on formulation. In this work, process analytical technology pat based approaches for controlling the polymorphism and crystal size of a nonsteroidal antiinflammatory drug piroxicam during batch cooling crystallization has been investigated. Because solubility, crystal yield, and polymorphism are solvent dependent, solution recrystallization by solvent screening is of fundamental and of foremost importance to many chemical process industries. Polymorphisma critical consideration in pharmaceutical. Controlling polymorphism in pharmaceutical compounds can provide optimized solubility and bioavailability. Chemical engineering and chemical process technology vol. In 2006 a new crystal form was discovered of maleic acid124 years after the first crystal form was studied.
Polymorphisma critical consideration in pharmaceutical development, manufacturing, and stability welcome to pharmaceutical solids. Modern approach of pharmaceutical solids formulation. Polymorphic transformations in crystal growth 21 rvc figure 2. Polymorphism can potentially be found in any crystalline material. Polymorphism is the ability of a specific chemical composition to crystallize in more than one form. It is essential to understand the solidstate behavior. This column has been developed with the intention to help readers under. Analysis of crystal polymorphism by raman spectroscopy for. The different structures of such a chemical substance are. Polymorphism is defined as the ability of a solid material to exist in more than one form or crystal structure, whereas allotropy is defined as the property of some chemical elements to exist in two or more different forms, in the same physical state, known as allotropes of these elements. Polymorphism can be classified into two types according to their stability with respect to the different range of. For those in other disciplines, or in academia, wishing to get a perspective on industrial problems in crystallisation, polymorphism, salt formation etc and how to solve them, this would also be a valuable.
Polymorph properties should include the morphology of crystals, their crystallographic. Pdf polymorphism in molecular crystals is a prevalent phenomenon and is of great interest to the pharmaceutical community. Apr 11, 2014 chapter 1 why a new industrial chemical process could be needed. It describes the ability of a substance to exist as two or more crystalline phases that have different arrangements of the molecules in the solid state but are otherwise identical in terms of chemical content. It is particularly important in the development of pharmaceutical ingredients as different crystal form can have significantly different physical, chemical and biological properties and many drugs receive regulatory approval for only a single crystal form or polymorph. Polymorphism is the ability of a substance to crystallize in different crystal modifications, each of them having the same chemical structure but different arrangements or conformations of the molecules in the crystal lattice. Physicochemical properties of api impact on formulation development duk soon choi, ph. However, no relevant data can be found in the literature about its crystal polymorphism. This generally occurs as a response to changes in temperature or pressure or both. This column discusses scientific principles associated with pharmaceutical solids useful to practitioners in validation and compliance. Polymorphism is the ability of solid materials to exist in two or more crystalline forms with.
The different structures of such a chemical substance are called polymorphic forms, or polymorphs. This is a controversial area, but what everyone can agree on is that there are numerous cases where some particular crystal form of a compound has been prepared and characterized, but later on becomes far. Nov 26, 2019 and since these more stable crystal forms tend to have very different solubilities, the effect on a drug development program or in ritonavirs case, a drug that is already rolling off the manufacturing line. Voronoidirichlet tesselation as a tool for investigation of polymorphism in molecular crystals with c w h x n y o z composition and photochromic properties. It has critical implications in material design for specific functions in optoelectronics, pharmaceuticals, food emulsion and so on.
General introduction to polymorphism, crystal habits and morphology, salt and excipient selection, stability, solubility and other solid characterization elements impact on drug development important decision to make, formulation, process ability and upscale. Crystal polymorphism is a phenomenon where compounds with the same chemical formula can be crystallized into. Moreover, the development, manufacture, transportation, storage and supply of solid state formulations are simpler and less expensive in comparison to liquid state formulations nunn et al. Iv development of chemical processes herbert vogel encyclopedia of life support systems eolss the starting point is the laboratory equipment and the outcome of development is the production plant. Crystal polymorphism in chemical process development crystal polymorphism in chemical process development lee, alfred y erdemir, deniz. The crystal structure depends on the conditions such as temperature and pressure used in the. Polymorphism in processes of crystallization in solution. This contribution highlights the prevalence and importance of crystal polymorphism in drug development, briefly describes the solid form selection process, and provides case studies on controlling polymorphs from a chemical process development perspective. Prankerd, phd department of pharmaceutics faculty of pharmacy monash university melbourne australia.
Inconsistencies in the solid phase produced during the manufacturing and storage of drug substances and drug products may have severe consequences. Crystal polymorphism in chemical process development. The purpose of this paper was to present two anhydrous forms form i and form ii and a hydrate of bisoprolol fumarate substance. Physico chemical properties of api impact on formulation development duk soon choi, ph. Polymorphism is a common phenomenon with many crystalline solids in the pharmaceutical and fine chemical industry. Polymorphism is the ability of a solid substance to crystallise into more than one different crystal structure. Polymorphism in molecular crystals is a prevalent phenomenon and is of great interest to the pharmaceutical community. Polymorphism in organic crystals polymorphism, defined as the ability of a material to crystallize in different crystal structures i, is very often revealed in organic crystals. Pdf crystal polymorphism in chemical process development.
Concomitant polymorphism is headache for pharmaceutical industry which seeks. In this an crystal view point the writer makes an effort to prove the importance of polymorphism in pharmaceuticals and how it shows. However, the appropriate polymorph selection during drug development process to. Polymorphism types of polymorphismrelation between. Despite the potential implications, polymorphism is not always well understood. Crystallization of organic compounds wiley online books. Process analytical tools to control polymorphism and particle.
Analysis of crystal polymorphism by raman spectroscopy for medicine development application note introduction crystal polymorphism is a phenomenon where compounds with the same chemical formula can be crystallized into different crystal structures. Recent advances in the identification and prediction of polymorphs. Polymorphism occurs when a chemical compound crystallizes with different. Process analytical tools to control polymorphism and. Molecular interactions between solvent and pharmaceutical. It has been shown that around onethird of organic substances show crystalline polymorphism under normal pressure conditions. The conformational difference results principally from the thiophene torsion relative to the onitroaniline fragment, which leads to different crystal colors red, orange, and yellow. Scientists deliberately crystallize a desired polymorph to improve isolation properties, help overcome downstream process challenges, increase bioavailability or to prevent patent conflicts. Our experienced team can develop processes to overcome common process hurdles including safety, scalability and specialized purifications. It uses plenty of case studies and examples of crystallization processes, ranging from development through.
Acta crystallographica section b structural science 2012, 68 3, 305312. Jul 20, 2018 bisoprolol fumarate is a beta blockertype drug substance which has been well known for several decades. Process development strategy to ascertain reproducible api. Anhydrous and solvated forms among the various techniques used to enhance the solubility of poorly soluble drugs are physical and chemical modifications of the drug, and methods such as particle size reduction, salt formation, solid dispersion, use of surfactant, and complexation 23. 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. The search for crystal polymorphism of pharmaceutical compounds is important from the identification of crystal polymorphism and the contribution to the development of more effective pharmaceuticals. Bisoprolol fumarate is a beta blockertype drug substance which has been well known for several decades. Polymorphism in the pharmaceutical industry wiley online books.
The solidstate form is a key quality attribute of a crystalline product. In this chapter, a strategy for metastable phase crystallization will be discussed considering three processes in the effort to control the. Crystal polymorphism of sodium benzene1,3dicarboxy5sulfonate monohydrate. Polymorphic forms of bisoprolol fumarate springerlink. In materials science, polymorphism is the ability of a solid material to exist in more than one form or crystal structure. His principal area of research is the comparison of experimental xray diffraction data with computationally simulated data. Because solubility, polymorphism, crystallinity, and crystal habit are all solvent dependent, solvent screening is of fundamental and foremost importance to many chemical process industries, especially the pharmaceutical industry 4, 2022.
Dec 10, 2018 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. The prediction of crystal morphology, polymorphism, atomic displacement parameters adp, as well as the physicochemical properties of biologically active compounds are among his interests. In this work, two model pharmaceutical compounds, glycine and acetaminophen, were crystallized using a flow coating technique termed solution shearing to create thin films with controllable polymorphism. Solid state stability polymorphism ku scholarworks. Previously obtained results regarding the crystallization behavior of the different polymorphs of piroxicam in a smallscale 100 ml crystallizer have been used to. Crystal polymorphism in chemical process development annual. Filled with industrial examples emphasizing the practical applications of crystallization methodologies. Crystal polymorphism an overview sciencedirect topics. Crystalline forms were studied by various solidstate analytical methods. Solubility, polymorphism, crystallinity, and crystal habit. Influences of crystal anisotropy in pharmaceutical process. For chemists and engineers working in process research and development, or even in production, this is the best book on crystallisation. Crystal polymorphism in chemical process development the solidstate form is a key quality attribute of a crystalline product.
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