Narayan Variankaval

Bio: Narayan Variankaval is an academic researcher from Merck & Co.. The author has contributed to research in topics: Active ingredient & Crystallization. The author has an hindex of 14, co-authored 28 publications receiving 1400 citations. Previous affiliations of Narayan Variankaval include Massachusetts Institute of Technology & Georgia Institute of Technology.

Polymorphs, Salts, and Cocrystals: What’s in a Name?

Abstract: The December 2011 release of a draft United States Food and Drug Administration (FDA) guidance concerning regulatory classification of pharmaceutical cocrystals of active pharmaceutical ingredients (APIs) addressed two matters of topical interest to the crystal engineering and pharmaceutical science communities: (1) a proposed definition of cocrystals; (2) a proposed classification of pharmaceutical cocrystals as dissociable “API-excipient” molecular complexes. The Indo–U.S. Bilateral Meeting sponsored by the Indo–U.S. Science and Technology Forum titled The Evolving Role of Solid State Chemistry in Pharmaceutical Science was held in Manesar near Delhi, India, from February 2–4, 2012. A session of the meeting was devoted to discussion of the FDA guidance draft. The debate generated strong consensus on the need to define cocrystals more broadly and to classify them like salts. It was also concluded that the diversity of API crystal forms makes it difficult to classify solid forms into three categories that...

From Form to Function: Crystallization of Active Pharmaceutical Ingredients

Abstract: Since the introduction of aspirin in 1899, and more particularly since the advent of antibiotic ‘‘wonder drugs’’ in the 1940s, society has come to rely on the widespread availability of therapeutic drugs at reasonable prices. It was a tremendous challenge to bring penicillin to market and could not have been done without the simultaneous development of both product and process under the inspired leadership of Howard Florey over a 10 year period starting in the early 1930s, as revealed in the riveting story told by Eric Lax. 1 In the interim, much has changed in drug development, but the timelines remain long, and the obstacles to success remain high. For drugs delivered to patients in crystalline form, the physical properties of the active pharmaceutical ingredient (API) including crystal form, size and shape have the potential to impact bioperformance, particularly for low-solubility compounds, where the rate-limiting-step in drug uptake may be the dissolution of the API in the gut. These physical properties of the API are often controlled in the final API crystallization step. Because most small molecule drugs (.90%) are delivered in crystalline form, and currently about 90% of new API’s being pursued are classified as having low solubility in water, a well-controlled crystallization of the API is often a vitally important operation in pharmaceutical manufacturing. Moreover, it is a difficult operation because of uncertainty in the crystal forms that will appear, and because of the many challenges associated with scaling-up crystallizations from laboratory to manufacturing scale. Although great emphasis is placed on the therapeutic and chemical discovery aspects of new APIs, it must be emphasized that the successful entities will eventually need to be manufactured. Pisano 2 has made a detailed study of the strategic value of process development and concludes that the benefits of a superior manufacturing process can include early product launch and consistent, higher product quality. Most companies seek to minimize manufacturing costs and maximize process portability by applying the simplest manufacturing process capable of producing their drug product with desired attributes. Because only 10% of the compounds in development survive the efficacy and safety hurdles in the clinic and become marketed drugs, there is also great value in minimizing R&D costs (including clinical trials), which are estimated to be about $1 billion per launch, with a remaining life protected on-patent of typically only 6–10 years. In this perspective, we describe the state-of-the-art in API crystal product and process design, highlight barriers that currently prevent the production of better, cheaper crystalline products, and give our best estimate of where the field is going and should go during the next decade.

Preparation and Solid-State Characterization of Nonstoichiometric Cocrystals of a Phosphodiesterase-IV Inhibitor and l-Tartaric Acid

Abstract: Evidence for a series of nonstoichiometric, isostructural, cocrystalline complexes of L-883555, a phosphodiesterase-IV inhibitor, and l-tartaric acid with stoichiometries ranging from 0.3:1 to 0.9:1 is reported here. The free base form of this compound had insufficient bioavailability and, hence, could not be developed as a candidate for safety assessment studies. Several l-tartaric acid complexes were produced during an attempted salt-formation process, with the objective of increasing the bioavailability. It was found that the amount of l-tartaric acid incorporated in the cocrystalline complexes could be controlled by adjusting the acid:base ratio in the reaction mixture without accompanying proton transfer between acid and base. Spectroscopic techniques were employed to locate the site of intermolecular interaction between the acid and base as the N-oxide group in the base and the carboxylic acid of l-tartaric acid. Thermal and spectroscopic analysis of the degradation behavior for the various complexe...

Surface-mediated nucleation in the solid-state polymorph transformation of terephthalic acid.

Abstract: A molecular mechanism for nucleation for the solid-state polymorph transformation of terephthalic acid is presented. New methods recently developed in our group, aimless shooting and likelihood maximization, are employed to construct a model for the reaction coordinate for the two system sizes studied. The reaction coordinate approximation is validated using the committor probability analysis. The transformation proceeds via a localized, elongated nucleus along the crystal edge formed by fluctuations in the supramolecular synthons, suggesting a nucleation and growth mechanism in the macroscopic system.

Pharmaceutical Cocrystals and Their Physicochemical Properties

Abstract: 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.

Strategies to Address Low Drug Solubility in Discovery and Development

Abstract: 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.

Crystal engineering: from molecule to crystal.

Abstract: How do molecules aggregate in solution, and how do these aggregates consolidate themselves in crystals? What is the relationship between the structure of a molecule and the structure of the crystal it forms? Why do some molecules adopt more than one crystal structure? Why do some crystal structures contain solvent? How does one design a crystal structure with a specified topology of molecules, or a specified coordination of molecules and/or ions, or with a specified property? What are the relationships between crystal structures and properties for molecular crystals? These are some of the questions that are being addressed today by the crystal engineering community, a group that draws from the larger communities of organic, inorganic, and physical chemists, crystallographers, and solid state scientists. This Perspective provides a brief historical introduction to crystal engineering itself and an assessment of the importance and utility of the supramolecular synthon, which is one of the most important concepts in the practical use and implementation of crystal design. It also provides a look to the future from the viewpoint of the author, and indicates some directions in which this field might be moving.

Catalytic Functionalization of Indoles in a New Dimension

Abstract: 140 years ago Adolf von Baeyer proposed the structure of a heteroaromatic compound which revolutionized organic and medical chemistry: indole. After more than a century, indole itself and the complexity of naturally occurring indole derivatives continue to inspire and influence developments in synthetic chemistry. In particular, the ubiquitous presence of indole rings in pharmaceuticals, agrochemicals, and functional materials are testament to the ever increasing interest in the design of mild and efficient synthetic routes to functionalized indole derivatives. This Review emphasizes the achievements in the selective catalytic functionalization of indoles (C-C bond-forming processes) over the last four years.