Over the last 20 years, the number of publications outlining the advances in design strategies, growing techniques, and characterization of cocrystals has continued to increase significantly within the crystal engineering field. However, only within the last decade have cocrystals found their place in pharmaceuticals, primarily due to their ability to alter physicochemical properties without compromising the structural integrity of the active pharmaceutical ingredient (API) and thus, possibly, the bioactivity. This review article will highlight and discuss the advances made over the last 10 years pertaining to physical and chemical property improvements through pharmaceutical cocrystalline materials and, hopefully, draw closer the fields of crystal engineering and pharmaceutical sciences.

Pharmaceutical Cocrystals and Their Physicochemical Properties

Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to "design in" acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40% of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.

Strategies to Address Low Drug Solubility in Discovery and Development

Pharmaceutical cocrystals can improve solubility, dissolution, and bioavailability of poorly water soluble drugs. However, true cocrystal solubility is not readily measured for highly soluble cocrystals because they can transform to the most stable drug form in solution. The objectives of this study are to develop a method to estimate the cocrystal solubility in pure solvent and establish the influence of constituent drug and ligand (i.e., coformer) properties. Cocrystal solubility and solubility product were derived from transition concentration measurements where a solution is in equilibrium with solid drug and cocrystal. Transition concentrations and solubilities are reported for carbamazepine cocrystals in water, ethanol, isopropanol, and ethyl acetate. The aqueous solubility for seven carbamazepine cocrystals was estimated to be 2−152 times greater than the solubility of the stable carbamazepine dihydrate form. Cocrystal solubility is shown to be directly proportional to the solubility of constituent...

Solubility Advantage of Pharmaceutical Cocrystals

Crystallisation is at the heart of various scientific disciplines, but still the understanding of the molecular mechanisms underlying phase separation and the formation of the first solid particles in aqueous solution is rather limited. In this review, classical nucleation theory, as well as established concepts of spinodal decomposition and liquid–liquid demixing, is introduced together with a description of the recently proposed pre-nucleation cluster pathway. The features of pre-nucleation clusters are presented and discussed in relation to recent modifications of the classical and established models for phase separation, together with a review of experimental work and computer simulations on the characteristics of pre-nucleation clusters of calcium phosphate, calcium carbonate, iron(oxy)(hydr)oxide, silica, and also amino acids as an example of small organic molecules. The role of pre-nucleation clusters as solute precursors in the emergence of a new phase is summarized, and the link between the chemical speciation of homogeneous solutions and the process of phase separation via pre-nucleation clusters is highlighted.

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Pre-nucleation clusters as solute precursors in crystallisation

A brief and systematic overview of recent advances in understanding the mechanism of mechanochemical cocrystallization at macroscopic (bulk phase transformations) and microscopic levels (molecular recognition) is given. The review particularly addresses neat and liquid-assisted grinding approaches to cocrystal formation.

Recent Advances in Understanding the Mechanism of Cocrystal Formation via Grinding

We describe the use of ternary, isothermal phase diagrams of co-crystal-forming systems as a basis for understanding current crystallization methodologies and for experimental design in the preparation of co-crystals.

Making Co-crystals-The utility of ternary phase diagrams

This contribution concerns the issue of crystal nucleation in the polymorphic and hydrate forming system inosine–water. A combination of computational and experimental tools have been used to explore the relationship between solution phase inosine species and the structural synthons as found in its crystal structures. It is evident that the initial nucleation of a metastable polymorph at temperatures above 10 °C is directed by dimeric self-association as revealed through proton NMR. At lower temperatures a dihydrate structure becomes the most stable solid phase and in this region of the phase diagram this is the only form that appears even though the solution species remain unchanged. This can only be rationalised in terms of a combination of water binding to the solution dimers and the thermodynamic stability of the hydrate crystal structure.

The nucleation of inosine: the impact of solution chemistry on the appearance of polymorphic and hydrated crystal forms.

ADVERTISEMENT RETURN TO ISSUEPREVEditorialNEXTCrystal Chemist, Crooner, Coach: A Transform Tribute to Professor Roger J. DaveyÖrn Almarsson*Örn Almarsson*Email: [email protected]More by Örn Almarssonhttps://orcid.org/0000-0002-3102-0691, Sherry CollierSherry CollierMore by Sherry Collier, Matthew L. PetersonMatthew L. PetersonMore by Matthew L. Peterson, Magali B. HickeyMagali B. HickeyMore by Magali B. Hickey, Eugene Y. CheungEugene Y. CheungMore by Eugene Y. Cheung, Mark OliveiraMark OliveiraMore by Mark Oliveira, Renato A. ChiarellaRenato A. ChiarellaMore by Renato A. Chiarellahttps://orcid.org/0000-0002-7603-2442, and Edwin A. CollierEdwin A. CollierMore by Edwin A. CollierCite this: Cryst. Growth Des. 2022, 22, 6, 3575–3578Publication Date (Web):May 9, 2022Publication History Published online9 May 2022Published inissue 1 June 2022https://doi.org/10.1021/acs.cgd.1c01399Copyright © Published 2022 by American Chemical SocietyRIGHTS & PERMISSIONSArticle Views543Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (4 MB) Get e-AlertsSUBJECTS:Crystallization,Crystals,Pharmaceuticals,Pharmaceutics,Salts Get e-Alerts 

https://pubs.acs.org/doi/pdf/10.1021/acs.cgd.1c01399

Crystal Chemist, Crooner, Coach: A Transform Tribute to Professor Roger J. Davey

In the pharmaceutical industry, tablets are a common dosage form. As part of the manufacturing process, powder in a tablet press passes through a feeding system called the feed-frame before reaching the die cavity. Under different manufacturing conditions (e.g., paddle speed, turret speed), issues such as segregation of powder blend components, over lubrication, and drug particle attrition often occur in the tablet press feed-frame, which affect the final drug product quality. Therefore, developing a particle-scale understanding of powder behavior in a feed-frame is essential. This paper used the discrete element method (DEM) to study powder flow in the feed-frame of a kg-pharma RoTab tablet press. Simulation results show that an increase in paddle speed has less effect on tablet mass than turret speed and that an increase in turret speed reduces tablet mass and increases variability in the tablet mass. The effect of paddle speed and turret speed on the API content in the tablet is small, but large paddle speeds exacerbate the segregation of powder blend components in the feed frame, increase particle traveled distance, particle shear work, and torque on the paddle wheel, thereby increasing particle over lubrication and attrition. However, the increase in paddle speed reduces the mean residence time of drug particles and prevents over lubrication at low turret speeds. Increasing the turret speed reduces tablet mass, particle shear work, paddle torque, and mean residence time. Although increasing turret speed can effectively prevent particle attrition and over lubrication, short residence times are not conducive to mixing excipients and API components, leading to higher tablet mass variability. This study not only gives us a particle-level insight into the process but can also be used to inform and optimize the design of experimental studies.

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Particle Scale Insights into a KG-Pharma RoTab Tablet Press Feed-Frame System Using the Discrete Element Method (DEM) Modeling

The present invention relates to a novel crystal of the Active Pharmaceutical Ingredient (API) N-[[(5S)-3 -[4-(2,6-dihydro-2-methylpyrrolo[3,4-c]pyrazol-5(4H)-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, methods for the preparation of this crystal, pharmaceutical compositions comprising this crystal, and methods of treating a patient with this crystal.

Renato A. Chiarella

Papers

Making Co-crystals-The utility of ternary phase diagrams

The nucleation of inosine: the impact of solution chemistry on the appearance of polymorphic and hydrated crystal forms.

Crystal Chemist, Crooner, Coach: A Transform Tribute to Professor Roger J. Davey

Particle Scale Insights into a KG-Pharma RoTab Tablet Press Feed-Frame System Using the Discrete Element Method (DEM) Modeling

Novel crystal of n-[[(5s)-3-[4-(2,6-dihydro-2-methylpyrrolo[3,4-c]pyrazol-5(4h)-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide