Applications of the crystallization process in the pharmaceutical industry (original) (raw)
A Brief Review On Pharmaceutical Co-crystals
2021
Recent studies has found that, discovering and developing novel medications is insufficient to attain therapeutic excellence and gain market economies. As a result, changed formulations of currently available medications are getting more significant. Also, poor water solubility and inadequate bioavailability of an active medicinal ingredient are two factors that limit the growth of a new product. The pharmacological action of the pharmaceutically active ingredient is unaffected by co-crystallization, with pharmaceutically acceptable molecules, although it can improve physical qualities such as solubility, stability and rate of dissolution. Most importantly, it is possible to use co-crystal to generate novel pharmaceuticals with improved solubility, improving treatment efficiency and safety. The most significant factor in the production of co-crystal is thermodynamic stability. Co-crystal formation can be performed by Grinding Methods, Spray Drying Method, Solvent Evaporation Techniq...
Advanced Drug Delivery Reviews, 2004
The concepts of high-throughput (HT) screening and combinatorial synthesis have been integrated into the pharmaceutical discovery process, but are not yet commonplace in the pharmaceutical development arena. Emerging strategies to speed pharmaceutical development and capture solid form diversity of pharmaceutical substances have resulted in the emergence of HT crystallization technologies. The primary type of diversity often refers to polymorphs, which are different crystal forms of the same chemical composition. However, diverse salt forms, co-crystals, hydrates and solvates are also amenable to study in HT crystallization systems. The impact of form diversity encompasses issues of stability and bioavailability, as well as development considerations such as process definition, formulation design, patent protection and regulatory control. This review highlights the opportunities and challenges of HT crystallization technologies as they apply to pharmaceutical research and development. D
PhD Thesis - On the crystallization of pharmaceutical semicrystalline dispersions
2018
A general introduction of the research topic is presented in Chapter 1, starting with the identification of low aqueous solubility of drug compounds as currently one of the most frequent and greatest challenges the pharmaceutical industry is facing, followed by introducing solid dispersions as a powerful strategy to formulate poorly water soluble drugs. Subsequently, semicrystalline dispersions are discussed. Various aspects of these specific systems are discussed, including the structure of carrier and drug-carrier dispersions, the importance of both drug and carrier in dictating the behavior of the systems, the influence of drug-carrier composition and interactions, the crystallization and dissolution of carrier, the impact of polymer molecular weight and other factors. A background in solid state crystallization and polymorphism is also provided. Chapter 2 points out the overall and specific objectives of the project in order to expand our mechanistic understanding about the crystallization behavior of both drug and carrier in their binary semicrystalline dispersions. Investigation of the crystallization kinetics of solid dispersions made up of IMC and PEG containing high drug loadings is the focus of Chapter 3. In this chapter, differential scanning calorimetry and X-ray powder diffraction was used to describe the influence of drug loading on the crystallization behavior of dispersions made up of IMC and PEG. It has been found that increasing the IMC content resulted in stronger crystallization inhibition of the polymer. At 52% drug loading, the crystallization of PEG was completely inhibited. To the best of our knowledge, this is the first detailed investigation of the crystallization inhibition effect of a low molecular weight drug on a semicrystalline polymer in their dispersions. In mixtures containing up to 55% indomethacin, the dispersions exhibited distinct glass transition events resulting from amorphous-amorphous phase separation which generates polymer-rich and drug-rich domains upon the solidification of supercooled PEG whereas samples containing at least 60% drug showed a single amorphous phase during the period in which crystallization normally occurs. In Chapter 4, we study the possibility of drug-carrier interactions to explain the inhibition effect of IMC on PEG crystallization. We also aim to discover other potential PEG crystallization inhibitors. Drug-carrier interactions in both liquid and solid state were characterized by variable temperature Fourier transform infrared spectroscopy (FTIR) and cross-polarization magic angle spinning 13C nuclear magnetic resonance spectroscopy (CP/MAS NMR). In the liquid state, FTIR data showed evidence of the breaking of hydrogen bonds between IMC molecules to form interactions of the IMC monomer with PEG. The drug-carrier interactions were disrupted upon storage and polymer crystallization, resulting in segregation of IMC from PEG crystals. This process was further confirmed by 13C NMR since in the liquid state, when the IMC:PEG monomer units ratio was below 2:1, IMC signals were undetectable because of the loss of cross-polarization efficiency in the mobile IMC molecules upon attachment to PEG chains via hydrogen bonding. This suggested that each ether oxygen of the PEG unit could form hydrogen bonds with two IMC molecules. The NMR spectrum of IMC showed no change in solid dispersions with PEG upon storage, indicating the absence of interactions in the solid state, hence confirming previous studies. The drug-carrier interactions in the liquid state elucidated the crystallization inhibition effect of IMC on PEG as well as other semi-crystalline polymers such as poloxamer and Gelucire. However, hydrogen bonding was a necessary but apparently not a sufficient condition for the polymer crystallization inhibition. Screening of crystallization inhibitors of semi-crystalline polymers discovered numerous candidates that exhibit the same behavior as IMC, demonstrating a general pattern of polymer crystallization inhibition rather than a particular case. Furthermore, the crystallization inhibition effect of drugs on PEG was independent of the carrier molecular weight. Due to the fact that the appearance of metastable crystal polymorphs in pharmaceutical semicrystalline dispersions has been extensively reported in literature, yet no clarification of the mechanism of the polymorph formation was proposed, Chapter 5 aims to elucidate the polymorphism behavior of IMC as well as the mechanism of polymorph selection of drugs in these systems. IMC crystallized as either the α or τ form - a new metastable form, or a mixture of the two polymorphs in dispersions containing different drug loadings in PEG, poloxamer or Gelucire as the result of the variation in the mobility of drug molecules. As a general rule, low molecular mobility of the amorphous drug favors the crystallization into thermodynamically stable forms whereas metastable crystalline polymorphs are preferred when mobility of drug molecules is sufficiently high. This rule provides insight into the polymorph selection of numerous active pharmaceutical ingredients (APIs) in semicrystalline dispersions and can be used as a guide for polymorphic screening from melt crystallization by tuning the mobility of drug molecules. In addition, the drug crystallized faster while the polymer crystallized slower as the drug loading increased with the maxima of both drug and polymer crystallization rates in 70% indomethacin dispersions. Increasing the drug content in solid dispersions reduced the τ to α polymorphic transition rate, except when the more stable form being initially dominant. The segregation of τ and α polymorphs as well as the polymorphic transformation during storage led to the inherent inhomogeneity of the semicrystalline dispersions. The microstructure of semicrystalline dispersions needs to be explored as it strongly affects macroscopic properties. Numerous factors have been reported that dictate the microstructure of these systems; nevertheless, the importance of the conformation of the polymer has never been elucidated. In Chapter 6, we investigate the microstructure of dispersions of PEG and APIs by small angle X-ray scattering and high performance differential scanning calorimetry. Polyethylene glycol with molecular weight of 2000 g/mol (PEG2000) and 6000 g/mol (PEG6000) exhibited remarkable discrepancy in the lamellar periodicity in dispersions with APIs which was attributed to the differences in their folding behavior. The long period of PEG2000 always decreased upon aging-induced exclusion of APIs from interlamellar region of extended chain crystals whereas the periodicity of PEG6000 may decrease or increase during storage as a consequence of the competition between the drug segregation and the lamellar thickening from non-integral folded into integral-folded chain crystals. The two processes were in turn significantly influenced by the crystallization tendency of the pharmaceutical compounds, drug-polymer interactions as well as the dispersion composition and crystallization temperature. These mechanistic findings expand our knowledge and understanding about the complex nature of pharmaceutical semicrystalline dispersions and are of significant importance for the preparation of systems with reproducible and consistent physicochemical properties and pharmaceutical performance. The key accomplishments of the current project are highlighted and discussed, and future research directions are suggested in Chapter 7.
2011
In pharmaceutical industries, active pharmaceutical ingredients (API) are made of crystals whose properties must be controlled because they influence the end-use properties of the drug. Even if crystal quality is mainly determined during the precipitation step, downstream processing also has an influence. In this study, the influence of washing on the crystal size and shape was analyzed. For the API being considered, different impurities have to be removed from the final suspension by filter cake washing. The efficiency of the washing steps was measured by different types of characterization on the solid phase (differential scanning calorimetry, scanning electron microscopy, and size distribution) and on the remaining filtrate (concentration of impurities). A second component also coprecipitates with the API. A specific study has been carried out on the withdrawal of this by-product and on its impact on the evolution of the crystalline form during washing steps. It was found that three filter cake washings allow us to remove all the impurities and to obtain a pure crystalline form.
Crystal growth of drug materials by spherical crystallization
2002
One of the crystal growth processes is the production of crystal agglomerates by spherical crystallization. Agglomerates of drug materials were developed by means of non-typical (magnesium aspartate) and typical (acetylsalicylic acid) spherical crystallization techniques. The growth of particle size and the spherical form of the agglomerates resulted in formation of products with good bulk density, flow, compactibility and cohesivity properties. The crystal agglomerates were developed for direct capsule-filling and tablet-making. r
New Trends in the Co-crystallization of Active Pharmaceutical Ingredients
Journal of Applied Pharmaceutical Science
Pharmaceutical materials science being a fundamental branch that continuously provides important insights, theories, and technologies to formulation sciences. The recent advances in this area have brought the possibility to produce pharmaceutical materials by design. In particular, the formation of co-crystals, i.e. crystalline molecular complexes of two-or more neutral molecules, represents a potential route to achieve pharmaceutical materials with improved properties of interest, including dissolution rate and stability under conditions of high relative humidity. Co-crystals consists of API and a stoichiometric amount of a pharmaceutically acceptable co-crystal former. Pharmaceutical co-crystals are nonionic supramolecular complexes and can be used to address physical property issues such as solubility, stability and bioavailability in pharmaceutical development without changing the chemical composition of the API. These can be constructed through several types of interaction, inc...
Solid state crystallinity, amorphous state, and its implications in the pharmaceutical process
International Journal of Pharmaceutical Sciences and Research
Many drugs exist in crystalline solid form due to reasons of stability and ease of handling during the various stages of drug development. Crystalline solids can exist in the form of polymorphs, solvates or hydrates. Phase transitions such as polymorph inter-conversion, formation of hydrates, desolvation of solvates, and conversion of the crystalline to amorphous form may occur during various pharmaceutical processes. This could change the dissolution rate and transport characteristics of the drug. The current focus of research in the area is to understand the origins of polymorphism at the molecular level, and to predict and prepare the most stable polymorph of the drug. The aim of this review is to understand the recent development in the area of solid state crystallinity, amorphous state and to address the current challenges faced by pharmaceutical formulation, process development scientists and to anticipate future developments.
IJPSM, 2021
Solubility is an important parameter for the bioavailability of drugs that are difficult to dissolve. Natural compounds that are included in class II in the Biopharmaceutics Classification System (BCS) are Apigenin, Quercetin, Genistein, Curcumin, and Piperin. These drugs have low solubility in water and high permeability so that they affect the dissolution rate and as well as their bioavailability, to increase the solubility they are made with multicomponent crystals. This review aims to provide information on the method of making crystal multicomponent to increase the solubility and dissolution rate of BCS II drugs. Several methods that can be used in multicomponent are solvent drop grinding, solvent evaporation, assisted grinding, and slurry. The results showed that multicomponent crystals using several methods could increase the solubility and dissolution rates.
2010
Pharmaceutical crystallisation operation is often critical because it determines product properties, such as the crystal size distribution (CSD) and polymorphic form, that can influence the subsequent downstream operations and the product therapeutic performance. Driven by the United States Food and Drug Administration's (FDA) Process Analytical Technology (PAT) initiative and the Quality-by-Design (QbD) Table of Contents v References 184 Appendix A Crystallographic data for sulfathiazole in Cambridge Structural Database. 202 Appendix B PXRD patterns for sulfathiazole raw material from Sigma 206 Appendix C Experimental determination of solubility of a solute in solvent(s). 208 Appendix D Experimental solubility data for sulfathiazole in sec-butanol, acetonitrile, isopropanol and water. 210 Appendix E Solubility curve of glycine in water. 211 Appendix F Crystallisation control interface used in the DNC experiments. 212 Appendix G Derivation for the calculation of the trajectory solution concentrations due to the dilution as a result of the antisolvent addition.
Spherical crystallization of drugs
Acta Pharmaceutica, 2000
Spherical crystallization of drugs Spherical crystallization of drugs is the process of obtaining larger particles by agglomeration during crystallization. The most common techniques used to obtain such particles are spherical agglomeration and quasi-emulsion solvent diffusion. Ammonia diffusion systems and crystallo-co-agglomeration are extensions of these techniques. By controlling process parameters during crystallization, such as temperature, stirring rate, type and amount of solvents, or excipient selection, it is possible to control the formation of agglomerates and obtain spherical particles of the desired size, porosity, or hardness. Researchers have reported that the particles produced have improved micromeritic, physical, and mechanical properties, which make them suitable for direct compression. In some cases, when additional excipients are incorporated during spherical crystallization, biopharmaceutical parameters including the bioavailability of drugs can also be tailored.